CN106045967B - Substituted heterocyclic compounds and their application in medicine - Google Patents
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Abstract
Translated fromChineseDescription
Translated fromChinese技术领域technical field
本发明属于药物技术领域，具体涉及用于治疗阿尔茨海默症的化合物、包含所述化合物的药物组合物及其用途。特别地，本发明所述的化合物是可以作为5-HT6受体拮抗剂的取代杂环化合物。The present invention belongs to the technical field of medicine, and specifically relates to a compound for treating Alzheimer's disease, a pharmaceutical composition comprising the compound and the use thereof. In particular, the compounds described in the present invention are substituted heterocyclic compounds that can act as5 -HT6 receptor antagonists.
背景技术Background technique
多种中枢神经系统疾病例如焦虑、抑郁等均与神经递质5-羟色胺(5-HT)或血清素的紊乱有关。作为脑中主要的调节性神经递质，神经递质5-羟色胺(5-HT)的功能是通过被称为5-HT1，5-HT2，5-HT3，5-HT4，5-HT5，5-HT6和5-HT7的大量受体家族介导的。基于脑中高水平的5-HT6受体mRNA，已经提出5-HT6受体可能在中枢神经系统病症的病理学和治疗中发挥作用。具体而言，已经确定5-HT6选择性配体对某些CNS(中枢神经系统)病症有潜在治疗作用，例如帕金森病、亨廷顿舞蹈病、焦虑症、抑郁症、躁狂抑郁症、精神病、癫痫、强迫症、偏头痛、阿尔茨海默症(认知记忆增强)、睡眠障碍、进食障碍如食欲缺乏和食欲过盛、惊恐发作、ADHD(注意力缺陷多动障碍)、注意力缺陷障碍、滥用药物例如可卡因、乙醇、尼古丁和苯并二氮杂
研究发现，已知的5-HT6受体选择性拮抗剂明显地提高额叶皮质中的谷氨酸和天冬氨酸的水平，而不提高去甲肾上激素、多巴胺或5-HT的水平。这种在记忆和认知过程中注意到的特定神经化学物质的选择性升高强烈地表明了5-HT6配体在认知中的作用(Dawson，L.A.；Nguyen，H.Q.；Li，P.，British Journal of Pharmacology，2000，130(1)，23-26)。用已知的选择性5-HT6受体拮抗剂对动物的记忆和学习进行的研究有一些积极的效果(Rogers，D.C.；Hatcher，P.D.；Hagan，J.J.，Society of Neuroscience，Abstracts，2000，26，680)。5-HT6配体的相关潜在治疗用途是治疗儿童和成年人的注意力缺陷症。因为5-HT6受体拮抗剂看起来提高了黑质纹状体多巴胺途径的活性，以及因为ADHD与尾状核中的异常有关(Ernst，M；Zametkin，A.J.；Matochik，J.H.；Jons，P.A.；Cohen,R.M.，Journal ofNeuroscience，1998，18(5)，5901-5907)，所以，5-HT6受体拮抗剂可以治疗注意力缺陷症。还已经确定5-HT6受体拮抗剂是治疗肥胖症的潜在有用化合物。参见例如Bentley等，Br.J.Pharmac.1999，增刊126；Bentley等，J.Psychopharmacol.1997，增刊A64：255；Wooley等，Neuropharmacology 2001，41：210-129和WO02098878。The study found that known 5-HT6 receptor-selective antagonists significantly increased glutamate and aspartate levels in the frontal cortex, but not norepinephrine, dopamine, or 5-HT. Level. This selective elevation of specific neurochemicals noted during memory and cognition strongly suggests a role for5 -HT6 ligands in cognition (Dawson, LA; Nguyen, HQ; Li, P. , British Journal of Pharmacology, 2000, 130(1), 23-26). Studies with known selective5 -HT6 receptor antagonists have had some positive effects on memory and learning in animals (Rogers, DC; Hatcher, PD; Hagan, JJ, Society of Neuroscience, Abstracts, 2000, 26 , 680). A related potential therapeutic use of5 -HT6 ligands is the treatment of attention deficit disorder in children and adults. Because5 -HT6 receptor antagonists appear to increase the activity of the nigrostriatal dopamine pathway, and because ADHD is associated with abnormalities in the caudate nucleus (Ernst, M; Zametkin, AJ; Matochik, JH; Jons, PA ; Cohen, RM, Journal of Neuroscience, 1998, 18(5), 5901-5907), therefore,5 -HT6 receptor antagonists can treat attention deficit disorder.5 -HT6 receptor antagonists have also been identified as potentially useful compounds for the treatment of obesity. See, eg, Bentley et al, Br. J. Pharmac. 1999, Suppl 126; Bentley et al, J. Psychopharmacol. 1997, Suppl A64:255; Wooley et al, Neuropharmacology 2001, 41:210-129 and WO02098878.
本发明提供了一类具有5-HT6受体拮抗活性的新化合物，具备较好的临床应用前景。与已有的同类化合物相比，本发明的化合物具有更好的药效、药代性质和/或毒理特性。The invention provides a new class of compounds with 5-HT6 receptor antagonistic activity, which has good clinical application prospect. Compared with the existing similar compounds, the compounds of the present invention have better pharmacodynamics, pharmacokinetic properties and/or toxicological properties.
发明内容SUMMARY OF THE INVENTION
本发明涉及一类取代的杂环化合物，与现有公开的化合物不同，其具有良好的5-HT6受体拮抗活性。并且，相较于现有的5-HT6受体拮抗剂，本发明化合物结构新颖，性质稳定，制备成本低，具有药效学和药代动力学优势，并且安全性良好，因此具备较好的临床应用前景。The present invention relates to a class of substituted heterocyclic compounds, which have good 5-HT6 receptor antagonistic activity, which is different from the compounds disclosed in the prior art. Moreover, compared with the existing 5-HT6 receptor antagonists, the compound of the present invention has novel structure, stable properties, low preparation cost, advantages in pharmacodynamics and pharmacokinetics, and good safety, so it has better prospects for clinical application.
本发明化合物和包含所述化合物的药物组合物对5-HT6受体有较好的亲和作用，用于治疗与5-HT6受体有关的疾病，特别是对阿尔茨海默症有较好的治疗效果。The compounds of the present invention and the pharmaceutical compositions containing the compounds have good affinity for 5-HT6 receptors, and are used for the treatment of diseases related to 5-HT6 receptors, especially for Alzheimer's disease. better treatment effect.
一方面，本发明涉及一种化合物，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolites, pharmaceutically acceptable salts or prodrugs,
其中，
X为-O-、-NRx-、-S-、-C(＝O)-、-CH2-或-CHRy-；X is -O-, -NRx-, -S-, -C(=O)-,-CH2- or-CHRy- ;
n为1、2、3或4；n is 1, 2, 3 or 4;
m为0、1、2、3或4；和m is 0, 1, 2, 3, or 4; and
各R1、R2、R3、R4、R5、R6、R7、R8、R9、Rx和Ry具有如本发明所述的含义。Each of R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8 , R9 , Rx and Ry has the meaning as described herein.
在一实施方案中，R1、R2、R3、R4和R5各自独立地为H、D、F、Cl、Br、I、-CN、-NO2、-OH、-NRaRb、-C(＝O)Rc、-S(＝O)2Rc、-C(＝O)NRaRb、-S(＝O)2NRaRb、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6烷硫基、(C3-C8环烷基)-(C0-C6亚烷基)-、(C2-C10杂环基)-(C0-C6亚烷基)-、(C6-C10芳基)-(C0-C6亚烷基)-或(C1-C9杂芳基)-(C0-C6亚烷基)-，其中所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6烷硫基、(C3-C8环烷基)-(C0-C6亚烷基)-、(C2-C10杂环基)-(C0-C6亚烷基)-、(C6-C10芳基)-(C0-C6亚烷基)-和(C1-C9杂芳基)-(C0-C6亚烷基)-独立任选地被一个或多个独立选自D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-COOH、氧代(＝O)、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基或C1-C6烷氨基的取代基所取代；和各Ra、Rb和Rc具有如本发明所述的含义。In one embodiment, R1 , R2 , R3 , R4 , and R5 are each independently H, D, F, Cl, Br, I, -CN, -NO2 , -OH, -NRa Rb , -C(=O)Rc , -S(=O)2 Rc , -C(=O)NRa Rb , -S(=O)2 NRa Rb , C1 -C6 alkane base, C2 -C6 alkenyl, C2 -C6 alkynyl, C1 -C6 alkoxy, C1 -C6 alkylthio, (C3 -C8 cycloalkyl)-(C0 -C6 alkylene)-, (C2 -C10 heterocyclyl)-(C0 -C6 alkylene)-, (C6 -C10 aryl)-(C0 -C6 alkylene) base)- or (C1 -C9 heteroaryl)-(C0 -C6 alkylene)-, wherein said C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C1 -C6 alkoxy, C1 -C6 alkylthio, (C3 -C8 cycloalkyl)-(C0 -C6 alkylene)-, (C2 -C10 heterocyclyl)-(C0 -C6 alkylene)-, (C6 -C10 aryl)-(C0 -C6 alkylene)- and (C1 -C9 heteroaryl) -(C0 -C6 alkylene)- independently optionally selected from one or more independently selected from D, F, Cl, Br, I, -CN,-NO2 ,-NH2 , -OH, -SH , -COOH, oxo (=O), C1 -C6 alkyl, C1 -C6 alkoxy, C1 -C6 alkylthio or C1 -C6 alkylamino substituents; and each of Ra , Rb and Rc has the meaning as described in the present invention.
在一实施方案中，各R6和R7独立地为H、D、F、Cl、Br、I、-CN、-NH2、-OH、-COOH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷氨基、C1-C6烷硫基、(C3-C8环烷基)-(C0-C6亚烷基)-、(C2-C10杂环基)-(C0-C6亚烷基)-、(C6-C10芳基)-(C0-C6亚烷基)-或(C1-C9杂芳基)-(C0-C6亚烷基)-。In one embodiment, each R6 andR7 is independently H, D, F, Cl, Br, I, -CN,-NH2 , -OH, -COOH,C1 -C6 alkyl,C2 -C6 alkenyl, C2 -C6 alkynyl, C1 -C6 haloalkyl, C1 -C6 alkoxy, C1 -C6 haloalkoxy, C1 -C6 alkylamino, C1 -C6 alkylthio, (C3 -C8 cycloalkyl)-(C0 -C6 alkylene)-, (C2 -C10 heterocyclyl)-(C0 -C6 alkylene) )-, (C6 -C10 aryl)-(C0 -C6 alkylene)- or (C1 -C9 heteroaryl)-(C0 -C6 alkylene)-.
在一实施方案中，R8为D、C2-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、(C3-C8环烷基)-(C0-C6亚烷基)-、(C2-C10杂环基)-(C0-C6亚烷基)-、(C6-C10芳基)-(C0-C6亚烷基)-或(C1-C9杂芳基)-(C0-C6亚烷基)-，其中所述C2-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、(C3-C8环烷基)-(C0-C6亚烷基)-、(C2-C10杂环基)-(C0-C6亚烷基)-、(C6-C10芳基)-(C0-C6亚烷基)-和(C1-C9杂芳基)-(C0-C6亚烷基)-独立任选地被一个或多个独立选自D、-CN、-NO2、-SH、-COOH、氧代(＝O)、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C1-C6烷硫基或C1-C6烷氨基的取代基所取代。In one embodiment, R8 is D, C2 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C1 -C6 haloalkyl, (C3 -C8 ring Alkyl)-(C0 -C6 alkylene)-, (C2 -C10 heterocyclyl)-(C0 -C6 alkylene)-, (C6 -C10 aryl)-( C0 -C6 alkylene)- or (C1 -C9 heteroaryl)-(C0 -C6 alkylene)-, wherein said C2 -C6 alkyl, C2 -C6 Alkenyl, C2 -C6 alkynyl, C1 -C6 haloalkyl, (C3 -C8 cycloalkyl)-(C0 -C6 alkylene)-, (C2 -C10 heterocycle base)-(C0 -C6 alkylene)-, (C6 -C10 aryl)-(C0 -C6 alkylene)- and (C1 -C9 heteroaryl)-(C0 -C6 alkylene) - independently optionally by one or more independently selected from D, -CN,-NO2 , -SH, -COOH, oxo (=O),C1 -C6 alkyl , C1 -C6 alkoxy, C1 -C6 haloalkyl, C1 -C6 haloalkoxy, C1 -C6 alkylthio or C1 -C6 alkylamino substituent.
在一实施方案中，各R9独立地为H、D、F、Cl、Br、I、-CN、-NO2、-OH、-NRaRb、-C(＝O)Rc、-S(＝O)2Rc、-C(＝O)NRaRb、-S(＝O)2NRaRb、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6氨基烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷硫基、C1-C6卤代烷硫基、(C3-C8环烷基)-(C0-C6亚烷基)-、(C2-C10杂环基)-(C0-C6亚烷基)-、(C6-C10芳基)-(C0-C6亚烷基)-或(C1-C9杂芳基)-(C0-C6亚烷基)-；和各Ra、Rb和Rc具有如本发明所述的含义。In one embodiment, eachR9 is independently H, D, F, Cl, Br, I, -CN,-NO2 , -OH,-NRaRb , -C( =O)Rc , - S(=O)2 Rc , -C(=O)NRa Rb , -S(=O)2 NRa Rb , C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C1 -C6 haloalkyl, C1 -C6 aminoalkyl, C1 -C6 alkoxy, C1 -C6 haloalkoxy, C1 -C6 alkylthio, C1 -C6 haloalkylthio, (C3 -C8 cycloalkyl)-(C0 -C6 alkylene)-, (C2 -C10 heterocyclyl)-(C0 -C6 alkylene alkyl)-, (C6 -C10 aryl)-(C0 -C6 alkylene)- or (C1 -C9 heteroaryl)-(C0 -C6 alkylene)-; and each of Ra , Rb and Rc has the meaning as described in the present invention.
在一实施方案中，Rx和Ry各自独立地为D、F、Cl、Br、I、-CN、-NH2、-NO2、-OH、-COOH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6氨基烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷硫基、C1-C6卤代烷硫基、(C3-C8环烷基)-(C0-C6亚烷基)-、(C2-C10杂环基)-(C0-C6亚烷基)-、(C6-C10芳基)-(C0-C6亚烷基)-或(C1-C9杂芳基)-(C0-C6亚烷基)-。In one embodiment,Rx andRy are each independently D, F, Cl, Br, I, -CN,-NH2 ,-NO2 , -OH, -COOH,C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C1 -C6 haloalkyl, C1 -C6 aminoalkyl, C1 -C6 alkoxy, C1 -C6 haloalkoxy , C1 -C6 alkylthio, C1 -C6 haloalkylthio, (C3 -C8 cycloalkyl)-(C0 -C6 alkylene)-, (C2 -C10 heterocycle base)-(C0 -C6 alkylene)-, (C6 -C10 aryl)-(C0 -C6 alkylene)- or (C1 -C9 heteroaryl)-(C0 -C6 alkylene)-.
在一实施方案中，各Ra、Rb和Rc独立地为H、-OH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、(C3-C8环烷基)-(C0-C6亚烷基)-、(C2-C10杂环基)-(C0-C6亚烷基)-、(C6-C10芳基)-(C0-C6亚烷基)-或(C1-C9杂芳基)-(C0-C6亚烷基)-。In one embodiment, each of Ra , Rb and Rc is independently H, -OH, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C1 - C6 haloalkyl, C1 -C6 alkoxy, C1 -C6 haloalkoxy, (C3 -C8 cycloalkyl)-(C0 -C6 alkylene)-, (C2 - C10 heterocyclyl)-(C0 -C6 alkylene)-, (C6 -C10 aryl)-(C0 -C6 alkylene)- or (C1 -C9 heteroaryl)- )-(C0 -C6 alkylene)-.
在一实施方案中，R1、R2、R3、R4和R5各自独立地为H、D、F、Cl、Br、I、-CN、-NO2、-OH、-NRaRb、-C(＝O)Rc、-S(＝O)2Rc、-C(＝O)NRaRb、-S(＝O)2NRaRb、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4烷氧基、C1-C4烷硫基、(C3-C6环烷基)-(C0-C4亚烷基)-、(C2-C6杂环基)-(C0-C4亚烷基)-、(C6-C10芳基)-(C0-C4亚烷基)-或(C1-C5杂芳基)-(C0-C4亚烷基)-，其中所述C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4烷氧基、C1-C4烷硫基、(C3-C6环烷基)-(C0-C4亚烷基)-、(C2-C6杂环基)-(C0-C4亚烷基)-、(C6-C10芳基)-(C0-C4亚烷基)-和(C1-C5杂芳基)-(C0-C4亚烷基)-独立任选地被一个或多个独立选自D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-COOH、氧代(＝O)、C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基或C1-C4烷氨基的取代基所取代；和各Ra、Rb和Rc具有如本发明所述的含义。In one embodiment, R1 , R2 , R3 , R4 , and R5 are each independently H, D, F, Cl, Br, I, -CN, -NO2 , -OH, -NRa Rb , -C(=O)Rc , -S(=O)2 Rc , -C(=O)NRa Rb , -S(=O)2 NRa Rb , C1 -C4 alkane base, C2 -C4 alkenyl, C2 -C4 alkynyl, C1 -C4 alkoxy, C1 -C4 alkylthio, (C3 -C6 cycloalkyl)-(C0 -C4 alkylene)-, (C2 -C6 heterocyclyl)-(C0 -C4 alkylene)-, (C6 -C10 aryl)-(C0 -C4 alkylene) base)- or (C1 -C5 heteroaryl)-(C0 -C4 alkylene)-, wherein said C1 -C4 alkyl, C2 -C4 alkenyl, C2 -C 4alkynyl, C1 -C4 alkoxy, C1 -C4 alkylthio, (C3 -C6 cycloalkyl)-(C0 -C4 alkylene)-, (C2-C6 heterocyclyl)-(C0 -C4 alkylene)-, (C6 -C10 aryl)-(C0 -C4 alkylene)- and (C1 -C5 heteroaryl) -(C0 -C4 alkylene)- independently optionally selected from one or more independently selected from D, F, Cl, Br, I, -CN,-NO2 ,-NH2 , -OH, -SH , -COOH, oxo (=O), C1 -C4 alkyl, C1 -C4 alkoxy, C1 -C4 alkylthio or C1 -C4 alkyl substituted with a substituent group; and each of Ra , Rb and Rc has the meaning as described in the present invention.
在一实施方案中，R1、R2、R3、R4和R5各自独立地为H、D、F、Cl、Br、I、-CN、-NO2、-OH、-NH2、-N(CH3)2、-C(＝O)CH3、-C(＝O)OH、-C(＝O)OCH3、-CONH2、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、-CF3或-OCF3。In one embodiment, R1 , R2 , R3 , R4 , and R5 are each independently H, D, F, Cl, Br, I, -CN, -NO2 , -OH, -NH2 , -N(CH3 )2 , -C(=O)CH3 , -C(=O)OH, -C(=O)OCH3 , -CONH2 , methyl, ethyl, n-propyl, isopropyl group, methoxy, ethoxy, n-propoxy, isopropoxy, -CF3 or -OCF3 .
在一实施方案中，各R6和R7独立地为H、D、F、Cl、Br、I、-CN、-NH2、-OH、-COOH、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷氨基、C1-C4烷硫基、(C3-C6环烷基)-(C0-C4亚烷基)-、(C2-C6杂环基)-(C0-C4亚烷基)-、(C6-C10芳基)-(C0-C4亚烷基)-或(C1-C5杂芳基)-(C0-C4亚烷基)-。In one embodiment, each R6 andR7 is independently H, D, F, Cl, Br, I, -CN,-NH2 , -OH, -COOH,C1 -C4 alkyl,C2 -C4 alkenyl, C2 -C4 alkynyl, C1 -C4 haloalkyl, C1 -C4 alkoxy, C1 -C4 haloalkoxy, C1 -C4 alkylamino, C1 -C4 alkylthio, (C3 -C6 cycloalkyl)-(C0 -C4 alkylene)-, (C2 -C6 heterocyclyl)-(C0 -C4 alkylene) )-, (C6 -C10 aryl)-(C0 -C4 alkylene)- or (C1 -C5 heteroaryl)-(C0 -C4 alkylene)-.
在一实施方案中，各R9独立地为H、D、F、Cl、Br、I、-CN、-NO2、-OH、-NRaRb、-C(＝O)Rc、-S(＝O)2Rc、-C(＝O)NRaRb、-S(＝O)2NRaRb、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4氨基烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷硫基、C1-C4卤代烷硫基、(C3-C6环烷基)-(C0-C4亚烷基)-、(C2-C6杂环基)-(C0-C4亚烷基)-、(C6-C10芳基)-(C0-C4亚烷基)-或(C1-C5杂芳基)-(C0-C4亚烷基)-；和各Ra、Rb和Rc具有如本发明所述的含义。In one embodiment, eachR9 is independently H, D, F, Cl, Br, I, -CN,-NO2 , -OH,-NRaRb , -C( =O)Rc , - S(=O)2 Rc , -C(=O)NRa Rb , -S(=O)2 NRa Rb , C1 -C4 alkyl, C2 -C4 alkenyl, C2 -C4 alkynyl, C1 -C4 haloalkyl, C1 -C4 aminoalkyl, C1 -C4 alkoxy, C1 -C4 haloalkoxy, C1 -C4 alkylthio, C1 -C4 haloalkylthio, (C3 -C6 cycloalkyl)-(C0 -C4 alkylene)-, (C2 -C6 heterocyclyl)-(C0 -C4 alkylene alkyl)-, (C6 -C10 aryl)-(C0 -C4 alkylene)- or (C1 -C5 heteroaryl)-(C0 -C4 alkylene)-; and each of Ra , Rb and Rc has the meaning as described in the present invention.
在一实施方案中，Rx和Ry各自独立地为D、F、Cl、Br、I、-CN、-NH2、-NO2、-OH、-COOH、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4氨基烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷硫基、C1-C4卤代烷硫基、(C3-C6环烷基)-(C0-C4亚烷基)-、(C2-C6杂环基)-(C0-C4亚烷基)-、(C6-C10芳基)-(C0-C4亚烷基)-或(C1-C5杂芳基)-(C0-C6亚烷基)-；和各Ra、Rb和Rc具有如本发明所述的含义。In one embodiment,Rx andRy are each independently D, F, Cl, Br, I, -CN,-NH2 ,-NO2 , -OH, -COOH,C1 -C4 alkyl, C2 -C4 alkenyl, C2 -C4 alkynyl, C1 -C4 haloalkyl, C1 -C4 aminoalkyl, C1 -C4 alkoxy, C1 -C4 haloalkoxy , C1 -C4 alkylthio, C1 -C4 haloalkylthio, (C3 -C6 cycloalkyl)-(C0 -C4 alkylene)-, (C2 -C6 heterocycle base)-(C0 -C4 alkylene)-, (C6 -C10 aryl)-(C0 -C4 alkylene)- or (C1 -C5 heteroaryl)-(C0 -C6alkylene )-; and each of Ra , Rb and Rc has the meaning as described in the present invention.
在一实施方案中，各Ra、Rb和Rc独立地为H、-OH、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、(C3-C6环烷基)-(C0-C4亚烷基)-、(C2-C6杂环基)-(C0-C4亚烷基)-、(C6-C10芳基)-(C0-C4亚烷基)-或(C1-C5杂芳基)-(C0-C4亚烷基)-。In one embodiment, each of Ra , Rb and Rc is independently H, -OH, C1 -C4 alkyl, C2 -C4 alkenyl, C2 -C4 alkynyl, C1 - C4 haloalkyl, C1 -C4 alkoxy, C1 -C4 haloalkoxy, (C3 -C6 cycloalkyl)-(C0 -C4 alkylene)-, (C2 - C6 heterocyclyl)-(C0 -C4 alkylene)-, (C6 -C10 aryl)-(C0 -C4 alkylene)- or (C1 -C5 heteroaryl)- )-(C0 -C4 alkylene)-.
在一实施方案中，各R6和R7独立地为H、D、F、Cl、Br、I、-CN、-NH2、-OH、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基或异丙氧基。In one embodiment, each R6 andR7 is independently H, D, F, Cl, Br, I, -CN,-NH2 , -OH, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy.
在一实施方案中，各R9独立地为H、D、F、Cl、Br、I、-CN、-NO2、-OH、-NH2、-N(CH3)2、-C(＝O)CH3、-C(＝O)OH、-C(＝O)OCH3、-CONH2、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、-CF3、-CH2CF3、-OCF3、-OCH2CF3或-OCH2CF2CHF2。In one embodiment, eachR9 is independently H, D, F, Cl, Br, I, -CN,-NO2 , -OH,-NH2 , -N(CH3 )2 , -C(= O)CH3 , -C(=O)OH, -C(=O)OCH3 , -CONH2 , methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy ,isopropoxy ,-CF3 ,-CH2CF3 ,-OCF3 ,-OCH2CF3or-OCH2CF2CHF2.
在一实施方案中，Rx和Ry各自独立地为D、F、Cl、Br、I、-CN、-NH2、-NO2、-OH、-COOH、甲基、乙基、正丙基或异丙基。In one embodiment,Rx andRy are each independently D, F, Cl, Br, I, -CN,-NH2 ,-NO2 , -OH, -COOH, methyl, ethyl, n-propyl radical or isopropyl.
在一实施方案中，各Ra、Rb和Rc独立地为H、-OH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基或异丙氧基。In one embodiment, each ofRa ,Rb , andRc is independently H, -OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy.
在一实施方案中，R8为D、C2-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、(C3-C6环烷基)-(C0-C4亚烷基)-、(C2-C6杂环基)-(C0-C4亚烷基)-、(C6-C10芳基)-(C0-C4亚烷基)-或(C1-C5杂芳基)-(C0-C4亚烷基)-，其中所述C2-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、(C3-C6环烷基)-(C0-C4亚烷基)-、(C2-C6杂环基)-(C0-C4亚烷基)-、(C6-C10芳基)-(C0-C4亚烷基)-和(C1-C5杂芳基)-(C0-C4亚烷基)-独立任选地被一个或多个独立选自D、-CN、-NO2、-SH、-COOH、氧代(＝O)、C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基、C1-C4烷硫基或C1-C4烷氨基的取代基所取代。In one embodiment, R8 is D, C2 -C4 alkyl, C2 -C4 alkenyl, C2 -C4 alkynyl, C1 -C4 haloalkyl, (C3 -C6 ring Alkyl)-(C0 -C4 alkylene)-, (C2 -C6 heterocyclyl)-(C0 -C4 alkylene)-, (C6 -C10 aryl)-( C0 -C4 alkylene)- or (C1 -C5 heteroaryl)-(C0 -C4 alkylene)-, wherein said C2 -C4 alkyl, C2 -C4 Alkenyl, C2-C4alkynyl ,C1-C4haloalkyl , (C3- C6cycloalkyl)-(C0- C4alkylene)-, (C2-C6heterocycle base)-(C0 -C4 alkylene)-, (C6 -C10 aryl)-(C0 -C4 alkylene)- and (C1 -C5 heteroaryl)-(C0 -C4 alkylene) - independently optionally by one or more independently selected from D, -CN,-NO2 , -SH, -COOH, oxo (=O),C1 -C4 alkyl , C1 -C4 alkoxy, C1 -C4 haloalkyl, C1 -C4 haloalkoxy, C1 -C4 alkylthio or C1 -C4 alkylamino substituent.
在一实施方案中，R8为D、乙基、正丙基、异丙基、-CHF2、-CF3、-CH2CHF2、-CH2CF3、-CHFCF3、-CF2CF3、-CF2CH3、-CF2CHF2、-CF2CH2CH3、-CF2CH2CF3、-CF2CH2CHF2、-CH2CHFCH3、-CH2CHFCHF2、-CH2CHFCF3、-CH2CF2CH3、-CH2CF2CF3或-CH2CF2CHF2。In one embodiment,R8 is D, ethyl, n-propyl , isopropyl,-CHF2 ,-CF3 ,-CH2CHF2 ,-CH2CF3 ,-CHFCF3 ,-CF2CF3 , -CF2 CH3 , -CF2 CHF2 , -CF2 CH2 CH3 , -CF2 CH2 CF3 , -CF2 CH2 CHF2 , -CH2 CHFCH3 , -CH2 CHFCHF2 ,-CH2CHFCF3,-CH2CF2CH3,-CH2CF2CF3or-CH2CF2CHF2.___
在一实施方案中，本发明所述的化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：In one embodiment, the compound described in the present invention is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvent of a compound having one of the following structures Compounds, metabolites, pharmaceutically acceptable salts or prodrugs:
另一方面，本发明涉及一种药物组合物，所述药物组合物包含本发明的化合物。In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention.
在一实施方案中，本发明所述的药物组合物，其进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或它们的任意组合。In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or any combination thereof.
在一实施方案中，本发明所述的药物组合物，其进一步包含附加治疗剂，所述附加治疗剂为治疗阿茨海默症的药物、治疗神经病症的药物或它们的组合。In one embodiment, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent, which is a drug for treating Alzheimer's disease, a drug for treating neurological disorders, or a combination thereof.
在一实施方案中，本发明所述的附加治疗剂为多奈哌齐(donepezil)、纳美芬(nalmefene)、利培酮(risperidone)、维他命E(Vitamin E)、AVN-211、AVN-101、RP-5063、tozadenant、PRX-3140、intepirdine、idalopirdine、他克林(tacrine)、卡巴拉汀(rivastigmine)、加兰他敏(galantamine)、美金刚(memantine)、米他扎平(Mirtazapine)、文拉法辛(venlafaxine)、去郁敏(desipramine)、去甲替林(nortriptyline)、唑吡坦(zolpidem)、佐匹克隆(zopiclone)、尼麦角林(nicergoline)、吡拉西坦(piracetam)、司来吉兰(selegiline)、己酮可可碱(pentoxifylline)或它们的任意组合。In one embodiment, the additional therapeutic agent of the present invention is donepezil, nalmefene, risperidone, vitamin E, AVN-211, AVN-101, RP -5063, tozadenant, PRX-3140, intepirdine, idalopirdine, tacrine, rivastigmine, galantamine, memantine, Mirtazapine, Lafaxine, desipramine, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam , selegiline, pentoxifylline, or any combination thereof.
另一方面，本发明涉及本发明化合物或药物组合物在制备药物中的用途，所述药物用于预防、治疗或减轻与5-HT6受体有关的疾病。In another aspect, the present invention relates to the use of a compound or a pharmaceutical composition of the present invention in the manufacture of a medicament for preventing, treating or alleviating a disease associated with the5 -HT6 receptor.
在一实施方案中，本发明涉及与5-HT6受体有关的疾病为CNS病症。In one embodiment, the present invention relates to a disease associated with the5 -HT6 receptor being a CNS disorder.
在一实施方案中，本发明涉及与5-HT6受体有关的疾病为CNS病症，其中所述的CNS病症为ADHD、焦虑、与精神紧张相关的疾病、精神分裂症、强迫观念与行为障碍、躁狂抑郁症、神经病症、记忆障碍、注意力缺陷障碍、帕金森病、肌萎缩性侧索硬化、阿尔茨海默症或亨廷顿舞蹈病。In one embodiment, the present invention relates to a disease associated with the5 -HT6 receptor being a CNS disorder, wherein the CNS disorder is ADHD, anxiety, stress-related disorders, schizophrenia, obsessive-compulsive and behavioral disorders , manic depression, neurological disorders, memory impairment, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's disease.
在一实施方案中，本发明涉及与5-HT6受体有关的疾病为胃肠道病症。In one embodiment, the present invention relates to a disorder associated with the5 -HT6 receptor being a gastrointestinal disorder.
在一实施方案中，本发明涉及与5-HT6受体有关的疾病为肥胖症。In one embodiment, the present invention relates to a disease associated with the5 -HT6 receptor being obesity.
本发明另一方面涉及式(I)所示的化合物的制备、分离和纯化的方法。Another aspect of the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。Any embodiment of any aspect of the invention may be combined with other embodiments so long as they do not appear to be inconsistent. Furthermore, in any embodiment of any aspect of the present invention, any technical feature may be applicable to that technical feature in other embodiments, as long as they do not contradict.
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他方面的内容将在下面作更加具体完整的描述。本说明书中的所有参考文献通过整体引用于此。The foregoing has outlined only certain aspects of the invention, but is not limited to these aspects. These and other aspects are described in more detail below. All references in this specification are hereby incorporated by reference in their entirety.
本发明详细说明书Detailed Description of the Invention
定义和一般术语Definitions and General Terms
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which are included within the scope of the present invention as defined by the claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, terms defined, uses of terms, techniques described, etc.), this Application shall prevail.
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of multiple separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,和“March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,JohnWiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。Unless otherwise stated, the following definitions as used herein shall apply. For the purposes of the present invention, chemical elements are in accordance with the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry may be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, Its entire contents are incorporated herein by reference.
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。As used herein, the articles "a", "an" and "the" are intended to include "at least one" or "one or more" unless stated otherwise or otherwise clearly contradicted by context. Thus, as used herein, these articles refer to one or more than one (ie, at least one) object of the article. For example, "a component" refers to one or more components, ie, there may be more than one component contemplated for use or use in the implementation of the described embodiments.
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open-ended expression, that is, it includes the contents specified in the present invention, but does not exclude other aspects.
术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。The term "stereoisomers" refers to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, etc. .
术语“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。The term "chirality" refers to a molecule that has the property of being non-superimposable with its mirror image; whereas "achiral" refers to a molecule that is superimposable with its mirror image.
术语“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。The term "enantiomer" refers to two nonsuperimposable, but mirror-image isomers of a compound.
术语“外消旋物”或“外消旋混合物”是指缺少光学活性的两个对映异构体的等摩尔混合物。The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers lacking optical activity.
术语“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。The term "diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.,McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；andEliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc,New York,1994。许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。Stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds" ", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and 1 or (+) and (-) are symbols used to designate the rotation of plane polarized light by the compound, where (-) or 1 indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。Any asymmetric atom (eg, carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched forms, such as (R)-, (S)- or (R,S)-configurations exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)-configuration 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。Depending on the choice of starting materials and process, the compounds of the present invention may be present as one of the possible isomers or as mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have the cis or trans configuration.
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。The resulting mixtures of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(lowenergy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution). For example, protontautomers (also known as prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况以及其中它不出现的情况。例如，“任选的键”是指该键可以存在或可以不存在，并且该描述包括单键、双键或三键。The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optional bond" means that the bond may or may not be present, and that the description includes single, double, or triple bonds.
术语“不饱和”或“不饱和的”表示部分含有一个或多个不饱和度。The term "unsaturated" or "unsaturated" means that a moiety contains one or more degrees of unsaturation.
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或未取代的”这个术语可以交换使用。一般而言，术语“取代”或“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是，但并不限于，D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、氧代(＝O)、羧基、烷基、烯基、炔基、烷氧基、烷氨基、烷硫基、卤代烷基、卤代烷氧基、羟基取代的烷基、羟基取代的卤代烷基、羟基取代的烷氧基、环烷基、杂环基、芳基、杂芳基、芳氧基、杂芳氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O)2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O)2-，等等。As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds. It is to be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" or "substituted" means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents can be substituted identically or differently at each position. The substituents described therein can be, but are not limited to, D, F, Cl, Br, I, -CN, -NO2 , -NH2 , -OH, oxo (=O), carboxyl, alkyl, Alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxy substituted alkyl, hydroxy substituted haloalkyl, hydroxy substituted alkoxy, cycloalkyl, heterocyclyl , aryl, heteroaryl, aryloxy, heteroaryloxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, Alkyl-S(=O)2- , hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2- , and the like.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。例如，结构式“-NRaRb”和结构式“-C(＝O)NRaRb”两者之间Ra和Rb的具体选项互相之间不受影响。In addition, it should be noted that, unless clearly stated otherwise, the description modes "each independently" and "...independently" and "...independently" used in the present invention can be interchanged, and both are interchangeable. It should be understood in a broad sense. It can either mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the specific options expressed between the same symbols do not affect each other. For example, the specific options for Ra and Rb between the structural formula "-NRa Rb " and the structural formula "-C(=O)NRa Rb " do not affect each other.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-C6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl,C4 alkyl,C5 alkyl andC6 alkyl groups.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the linking An alkylene group or an arylene group.
本发明使用的术语“烷基”或“烷基基团”，表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团含有1-20个碳原子。在一实施方案中，烷基基团含有1-12个碳原子；在另一实施方案中，烷基基团含有1-6个碳原子；在又一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。The term "alkyl" or "alkyl group" used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be is substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.
烷基基团的实例包含，但并不限于，甲基(Me、-CH3)，乙基(Et、-CH2CH3)，正丙基(n-Pr、-CH2CH2CH3)，异丙基(i-Pr、-CH(CH3)2)，正丁基(n-Bu、-CH2CH2CH2CH3)，异丁基(i-Bu、-CH2CH(CH3)2)，仲丁基(s-Bu、-CH(CH3)CH2CH3)，叔丁基(t-Bu、-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)，正己基(-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基(-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)，正庚基，正辛基，等等。Examples of alkyl groups include, but are not limited to, methyl (Me,-CH3 ), ethyl (Et, -CH2CH3), n-propyl (n- Pr,-CH2CH2CH3) ), isopropyl (i-Pr, -CH(CH3 )2 ), n-butyl (n-Bu, -CH2 CH2 CH2 CH3 ), isobutyl (i-Bu, -CH2 CH ) (CH3 )2 ), sec-butyl (s-Bu, -CH(CH3 )CH2 CH3 ), tert-butyl (t-Bu, -C(CH3 )3 ), n-pentyl (-CH 2CH2CH2CH2CH3),2 -pentyl (-CH(CH3)CH2CH2CH3) ,3- pentyl (-CH(CH2CH3)2) ,2 -methyl -2-butyl(-C(CH3)2CH2CH3),3 -methyl-2-butyl(-CH(CH3)CH(CH3)2),3-methyl -1- Butyl (-CH2CH2CH (CH3 )2 ),2 -methyl-1 -butyl (-CH2CH(CH3 )CH2CH3) , n- hexyl(-CH2CH2CH2CH2CH2CH3 ),2 -hexyl (-CH(CH3 )CH2CH2CH2CH3) ,3- hexyl (-CH(CH2CH3)(CH2CH2CH3)) , 2-methyl-2-pentyl(-C(CH3 )2CH2CH2CH3),3 -methyl-2 -pentyl(-CH(CH3)CH (CH3)CH2CH3 ), 4-methyl-2-pentyl (-CH(CH3 )CH2 CH(CH3 )2 ), 3-methyl-3-pentyl (-C(CH3 )(CH2 CH3 )2 ), 2-methyl-3-pentyl (-CH(CH2 CH3 )CH(CH3 )2 ), 2,3-dimethyl-2-butyl (-C(CH3 )2 CH (CH3 )2 ), 3,3-dimethyl-2-butyl (-CH(CH3 )C(CH3 )3 ), n-heptyl, n-octyl, and the like.
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明，亚烷基基团含有1-12个碳原子。在一实施方案中，亚烷基基团含有1-6个碳原子；在另一实施方案中，亚烷基基团含有1-4个碳原子；在又一实施方案中，亚烷基基团含有1-3个碳原子；还在一实施方案中，亚烷基基团含有1-2个碳原子。这样的实例包括亚甲基(-CH2-)，亚乙基(-CH2CH2-)，亚异丙基(-CH(CH3)CH2-)，等等。所述亚烷基基团任选地被一个或多个本发明所描述的取代基所取代。The term "alkylene" refers to a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms; in another embodiment, the alkylene group contains 1-4 carbon atoms; in yet another embodiment, the alkylene group A group contains 1-3 carbon atoms; in yet another embodiment, an alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH2- ), ethylene (-CH2CH2- ), isopropylidene (-CH(CH3) CH2-) , and the like. The alkylene group is optionally substituted with one or more substituents described herein.
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp2双键，其中，所述烯基基团任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“trans”的定位，或者“E”和“Z”的定位。The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp2 double bond, wherein the alkenyl group The group is optionally substituted with one or more substituents described herein, including the "cis" and "trans" positions, or the "E" and "Z" positions.
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团任选地被一个或多个本发明所描述的取代基所取代。The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group Optionally substituted with one or more substituents described herein.
术语“杂原子”表示一个或多个氧(O)，硫(S)，氮(N)，磷(P)或硅(Si)，包括氮(N)，硫(S)和磷(P)任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3，4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。The term "heteroatom" means one or more of oxygen (O), sulfur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), sulfur (S) and phosphorus (P) in any oxidation state; in the form of primary, secondary, tertiary amine and quaternary ammonium salts; or in the form in which the hydrogen on the nitrogen atom of the heterocycle is substituted, for example, N (as in 3,4-dihydro-2H-pyrrolyl N), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
术语“卤素”和“卤代”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
术语“卤代烷基”、“卤代烷氧基”或“卤代烷硫基”表示烷基、烷氧基或烷硫基基团被一个或多个卤素原子所取代，其中烷基、烷氧基和烷硫基基团具有本发明所述的含义，这样的实例包含，但并不限于，二氟甲基、三氟甲基、三氟甲氧基、2,2,2-三氟乙基、2,2,2-三氟乙氧基、2,2,3,3-四氟丙基、2,2,3,3-四氟丙氧基，等等。所述卤代烷基、卤代烷氧基或卤代烷硫基基团任选地被一个或多个本发明所描述的取代基所取代。The terms "haloalkyl," "haloalkoxy," or "haloalkylthio" mean an alkyl, alkoxy, or alkylthio group substituted with one or more halogen atoms, wherein alkyl, alkoxy, and alkylthio The radical group has the meaning described in the present invention, such examples include, but are not limited to, difluoromethyl, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethyl, 2, 2,2-trifluoroethoxy, 2,2,3,3-tetrafluoropropyl, 2,2,3,3-tetrafluoropropoxy, and the like. The haloalkyl, haloalkoxy or haloalkylthio group is optionally substituted with one or more substituents described herein.
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团任选地被一个或多个本发明描述的取代基所取代。The term "alkoxy" means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group is optionally substituted with one or more substituents described herein.
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH3)，乙氧基(EtO、-OCH2CH3)，1-丙氧基(n-PrO、n-丙氧基、-OCH2CH2CH3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH3)2)，1-丁氧基(n-BuO、n-丁氧基、-OCH2CH2CH2CH3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH2CH(CH3)2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH3)CH2CH3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH3)3)，1-戊氧基(n-戊氧基、-OCH2CH2CH2CH2CH3)，2-戊氧基(-OCH(CH3)CH2CH2CH3)，3-戊氧基(-OCH(CH2CH3)2)，2-甲基-2-丁氧基(-OC(CH3)2CH2CH3)，3-甲基-2-丁氧基(-OCH(CH3)CH(CH3)2)，3-甲基-l-丁氧基(-OCH2CH2CH(CH3)2)，2-甲基-l-丁氧基(-OCH2CH(CH3)CH2CH3)，等等。Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3 ), ethoxy (EtO, -OCH2 CH3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH2 CH2 CH3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3 )2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH2 CH2 CH2 CH3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2 CH(CH3 )2 ), 2-butanyl Oxy (s-BuO, s-butoxy, -OCH(CH3 )CH2 CH3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3 )3 ),1 -pentyloxy (n- pentyloxy, -OCH2CH2CH2CH2CH3),2- pentyloxy (-OCH(CH3)CH2CH2CH3) , 3-pentyloxy (-OCH(CH2 CH3 )2 ), 2-methyl-2-butoxy (-OC(CH3 )2 CH2 CH3 ), 3-methyl-2-butoxy group (-OCH(CH3 )CH(CH3 )2 ), 3-methyl-1-butoxy (-OCH2 CH2 CH(CH3 )2 ), 2-methyl-1-butoxy (-OCH2 CH(CH3 )CH2 CH3 ), etc.
术语“烷硫基”是指C1-C6直链或支链的烷基通过硫原子与分子其余部分相连。The term "alkylthio" refers to aC1 -C6 straight or branched chain alkyl group attached to the remainder of the molecule through a sulfur atom.
术语“烷氨基”或“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代，其中烷基基团具有如本发明所述的含义。The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino" wherein the amino group is independently substituted with one or two alkyl groups, respectively, where the alkyl group has the meaning as defined in the present invention.
术语“氨基烷基”包括被一个或多个氨基所取代的C1-C10直链或支链烷基基团。The term "aminoalkyl" includesC1 -C10 straight or branched chain alkyl groups substituted with one or more amino groups.
术语“环烷基”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环体系。The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms.
术语“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的单环、双环或三环体系，其中环上一个或多个原子独立地被杂原子所替换，所述杂原子具有如本发明所述的含义，环可以是完全饱和的或包含一个或多个不饱和度，但一个芳香性环都不能有。The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and both refer to a monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms in which one or more of the ring atoms is independently heterocyclic Atom is replaced, the heteroatom has the meaning as described in the present invention, the ring may be fully saturated or contain one or more degrees of unsaturation, but not an aromatic ring.
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中至少一个环是芳香族的。The term "aryl" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic .
术语“杂芳基”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少一个环是芳香族的，且至少一个环包含一个或多个杂原子。The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic, and At least one ring contains one or more heteroatoms.
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C1-C24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：Higuchi et al.,Pro-drugs as Novel Delivery Systems,Vol.14,A.C.S.Symposium Series；Roche et al.,ed.,Bioreversible Carriers in DrugDesign,American Pharmaceutical Association and Pergamon Press,1987；Rautio etal.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery,2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates,J.Med.Chem.,2008,51,2328-2345,每篇文献通过引用包含于此。The term "prodrug" as used in the present invention refers to the conversion of a compound into a compound of formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters can be used as prodrugs such as phenyl esters, aliphatic (C1 -C24 ) esters, acyloxymethyl esters, carbonic acid Esters, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent. A complete discussion of prodrugs can be found in the following literature: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series; Roche et al., ed., Bioreversible Carriers in DrugDesign, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al, Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328- 2345, each of which is hereby incorporated by reference.
本发明所使用的术语“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。The term "metabolite" as used in the present invention refers to a product obtained by metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,J.Pharmaceutical Sciences,66：1-19,1977所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N+(C1-C4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-C8磺酸化物和芳香磺酸化物。As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art as described in: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate, Malate, Mesylate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Palmitate, Pamoate, Pectate, Persulfate, 3-Phenylpropionic Acid Salt, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N+ (C1 -C4 alkyl)4 salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates,C1 -C8 sulfonates and aromatic sulfonates.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.
当所述溶剂为水时，可以使用术语“水合物”。在一实施方案中，一个本发明化合物分子可以与一个水分子相结合，比如一水合物；在另一实施方案中，一个本发明化合物分子可以与多于一个的水分子相结合，比如二水合物，在又一实施方案中，一个本发明化合物分子可以与少于一个的水分子相结合，比如半水合物。应注意，本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。When the solvent is water, the term "hydrate" may be used. In one embodiment, one molecule of the compound of the present invention may be associated with one molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate In yet another embodiment, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compounds.
术语“保护基团”或“PG”是指一个取代基与其他官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC,Boc)，苄氧羰基(CBZ,Cbz)和9-芴甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括三烷基甲硅烷基，乙酰基，苯甲酰基和苄基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH2CH2SO2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：Greene et al.,Protective Groups inOrganic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。The term "protecting group" or "PG" refers to a substituent group that is commonly used to block or protect specific functionality when it reacts with other functional groups. For example, "amino protecting group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenemethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. "Carboxyl protecting group" means that the substituent of the carboxyl group is used to block or protect the functionality of the carboxyl group. General carboxyl protecting groups include -CH2 CH2 SO2 Ph, cyanoethyl, 2-(trimethylsilane) yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) phosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference is made to: Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and Kocienski et al., Protecting Groups, Thieme, Stuttgart, 2005.
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。The term "treating" any disease or disorder, as used herein, in some embodiments refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.
术语“防止”或“预防”指获病或障碍的风险的减少(即：使疾病的至少一种临床症状在主体内停止发展，该主体可能面对或预先倾向面对这种疾病，但还没有经历或表现出疾病的症状)。The terms "prevent" or "prevent" refer to a reduction in the risk of acquiring a disease or disorder (ie: stopping the development of at least one clinical symptom of a disease in a subject who may be facing or predisposed to facing the disease, but also not experience or exhibit symptoms of disease).
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing Company,Easton,Pa.,(1985)；和“药用盐手册：性质、选择和应用(Handbook of PharmaceuticalSalts：Properties,Selection,and Use)”，Stahl and Wermuth(Wiley-VCH,Weinheim,Germany,2002)中可找到另外一些适宜盐的列表。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moieties, using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (eg, hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by The preparations are carried out by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, the use of non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is required. In, for example, "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use )", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) can find additional lists of suitable salts.
另外，本发明公开的化合物、包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶剂化的和未溶剂化的形式。In addition, the compounds disclosed herein, including their salts, can also be obtained in their hydrate form or in a form containing a solvent (eg, ethanol, DMSO, etc.) for their crystallization. Compounds of the present disclosure may form solvates, inherently or by design, with pharmaceutically acceptable solvents, including water; thus, the present invention is intended to include both solvated and unsolvated forms.
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如2H，3H，11C，13C，14C，15N，17O，18O，18F，31P，32P，35S，36Cl和125I。Any structural formula given herein is also intended to represent both isotopically unenriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures depicted by the general formulae given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes ofhydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H,3H ,11C ,13C ,14C ,15N ,17O ,18 O,18 F,31 P,32 P,35 S,36 Cl and125 I.
另一方面，本发明所述化合物包括同位素富集的本发明所定义的化合物，例如，其中存在放射性同位素，如3H，14C和18F的那些化合物，或者其中存在非放射性同位素，如2H和13C。该类同位素富集的化合物可用于代谢研究(使用14C)、反应动力学研究(使用例如2H或3H)、检测或成像技术，如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式(I)所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。In another aspect, the compounds of the present invention include isotopically enriched compounds as defined by the present invention, for example, those in which radioactive isotopes, such as3 H,14 C and18 F are present, or in which non-radioactive isotopes, such as2 H and13 C. Such isotopically enriched compounds can be used in metabolic studies (using14 C), reaction kinetic studies (using eg2 H or3 H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) for substrate tissue distribution measurements, or may be used in radiation therapy of patients.18 F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparation procedures of the present invention, using suitable isotopically labeled reagents to replace the previously used unlabeled reagents.
此外，较重同位素特别是氘(即，2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解，本发明中的氘被看做式(I)化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D2O、丙酮-d6、DMSO-d6的那些溶剂化物。In addition, substitution of heavier isotopes, particularly deuterium (ie,2 H or D), may provide certain therapeutic advantages that result from greater metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in the present invention is considered as a substituent of the compounds of formula (I). The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. If a substituent of a compound of the present invention is designated as deuterium, the compound has for each designated deuterium atom at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), At least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated) deuterium incorporation), an isotopic enrichment factor of at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg,D2O , acetone- d6,DMSO -d6.
除非其他方面表明，本发明的化合物所有合适的同位素变化、立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、盐和药学上可接受的前药都属于本发明的范围。Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention belong to scope of the present invention.
本发明公开化合物可含有不对称或手性中心，因此可以以不同的立体异构体形式存在。本发明旨在使式(I)所示化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体、阻转异构体和几何(或构象)异构体，以及它们的混合物如外消旋混合物，成为本发明的组成部分。The compounds disclosed herein may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention is intended to make all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers Compounds, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention. Additionally, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.
在本发明公开的结构中，当任意特定的手性原子的立体化学未指明时，则该结构的所有立体异构体都考虑在本发明之内，并且作为本发明公开化合物包括在本发明中。当立体化学被表示特定构型的实楔形线(solid wedge)或虚线指明时，则该结构的立体异构体就此明确和定义。In a structure disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated within the present invention and are included in the present invention as compounds disclosed herein . When stereochemistry is indicated by a solid wedge or a dashed line representing a particular configuration, then the stereoisomers of that structure are so identified and defined.
本发明化合物的氮氧化物也包含在本发明的范围之内。可以通过在升温下使用常用氧化剂(例如过氧化氢)，在有例如乙酸的酸存在下，氧化相应的含氮碱性物质，或者通过在适合的溶剂中与过酸反应，例如在二氯甲烷、乙酸乙酯或乙酸甲酯中与过乙酸反应，或在氯仿或二氯甲烷中与3-氯过氧苯甲酸反应，制备本发明化合物的氮氧化物。Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. Oxidation of the corresponding nitrogen-containing basic species can be accomplished by using common oxidizing agents such as hydrogen peroxide at elevated temperature in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as in dichloromethane , ethyl acetate or methyl acetate react with peracetic acid, or react with 3-chloroperoxybenzoic acid in chloroform or dichloromethane to prepare nitrogen oxides of the compounds of the present invention.
另一方面，本发明涉及制备式(I)所示化合物的中间体。In another aspect, the present invention relates to intermediates for the preparation of compounds of formula (I).
另一方面，本发明涉及式(I)所示化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I).
式(I)所示化合物可以以盐的形式存在。在一实施方案中，所述盐是指药学上可接受的盐。术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。在另一实施方案中，所述盐不一定是药学上可接受的盐，可以是用于制备和/或提纯式(I)所示化合物和/或用于分离本式(I)所示化合物的对映体的中间体。The compound represented by formula (I) may exist in the form of a salt. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated with it. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, but can be used for preparing and/or purifying the compound represented by the formula (I) and/or for isolating the compound represented by the formula (I) enantiomeric intermediates.
如果本发明的化合物是碱性的，则想得到的盐可以通过文献上提供的任何合适的方法制备得到，例如，使用无机酸，如盐酸，氢溴酸，硫酸，硝酸和磷酸等等。或者使用有机酸，如乙酸，马来酸，琥珀酸，扁桃酸，富马酸，丙二酸，丙酮酸，草酸，羟乙酸和水杨酸；吡喃糖酸，如葡萄糖醛酸和半乳糖醛酸；α-羟酸，如柠檬酸和酒石酸；氨基酸，如天门冬氨酸和谷氨酸；芳香族酸，如苯甲酸和肉桂酸；磺酸，如对甲苯磺酸，乙磺酸，等等。If the compounds of the present invention are basic, the desired salts can be prepared by any suitable method provided in the literature, for example, using mineral acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Alternatively use organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranonic acids such as glucuronic acid and galactose aldehydes; alpha-hydroxy acids, such as citric and tartaric acids; amino acids, such as aspartic acid and glutamic acid; aromatic acids, such as benzoic and cinnamic acids; sulfonic acids, such as p-toluenesulfonic acid, ethanesulfonic acid, and many more.
如果本发明的化合物是酸性的，则想得到的盐可以通过合适的方法制备得到，如，使用无机碱或有机碱，如氨(伯氨，仲氨，叔氨)，碱金属氢氧化物或碱土金属氢氧化物，等等。合适的盐包括，但并不限于，从氨基酸得到的有机盐，如甘氨酸和精氨酸，氨，如伯氨、仲氨和叔氨，和环状氨，如哌啶，吗啉和哌嗪等，和从钠，钙，钾，镁，锰，铁，铜，锌，铝和锂得到无机盐。If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, eg, using inorganic or organic bases such as ammonia (primary, secondary, tertiary), alkali metal hydroxides or alkaline earths Metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as piperidine, morpholine and piperazine etc., and inorganic salts are obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明化合物。在一实施方案中，本发明所述药物组合物，更进一步包括药学上可接受的载体、赋形剂、佐剂、溶媒或它们的组合。在另一实施方案中，药物组合物可以是液体、固体、半固体、凝胶或喷雾剂型。In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or a combination thereof. In another embodiment, the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
本发明化合物及药物组合物、制剂和给药Compounds of the Invention and Pharmaceutical Compositions, Formulations and Administration
当可用于治疗时，治疗有效量的式(I)化合物及其药学上可接受的盐可作为未加工的化学药品给予，还可作为药物组合物的活性成分提供。因此，本发明还提供一种药物组合物，包括式(I)所示的化合物或其单独的立体异构体，异构体的外消旋或非外消旋混合物或其药学上可接受的盐或溶剂化物。在本发明的一个实施方式中，所述药物组合物进一步包含至少一种药学上可接受的载体、辅剂、或赋形剂，以及任选地，其它的治疗和/或预防成分。When useful in therapy, a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable salt thereof can be administered as a raw chemical and can also be provided as an active ingredient of a pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition, comprising the compound represented by formula (I) or its individual stereoisomers, the racemic or non-racemic mixtures of the isomers or its pharmaceutically acceptable salt or solvate. In one embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant, or excipient, and optionally, other therapeutic and/or prophylactic ingredients.
合适的载体、辅剂和赋形剂剂对于本领域技术人员是熟知的并且详细描述于例如Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug DeliverySystems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al.,Remington：The Science and Practice of Pharmacy(2000)Lippincott,Williams&Wilkins,Philadelphia；和Rowe R.C.,Handbook of Pharmaceutical Excipients(2005)Pharmaceutical Press,Chicago中。Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel H.C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A.R. et al ., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.
包含本发明化合物或药物组合物给药的治疗方法，进一步包括对患者进行其他抗阿尔茨海默症药物(联合治疗)的给药，其中其他抗阿尔茨海默症的药物为多奈哌齐、纳美芬、利培酮、维他命E、AVN-211、AVN-101、RP-5063、tozadenant、PRX-3140、intepirdine、idalopirdine、他克林、卡巴拉汀、加兰他敏、美金刚、米他扎平、文拉法辛、去郁敏、去甲替林、唑吡坦、佐匹克隆、尼麦角林、吡拉西坦、司来吉兰、己酮可可碱或它们的任意组合。The treatment method comprising the administration of the compound of the present invention or the pharmaceutical composition further comprises the administration of other anti-Alzheimer's disease drugs (combination therapy) to the patient, wherein the other anti-Alzheimer's disease drugs are donepezil, Namet fen, risperidone, vitamin E, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, intepirdine, idalopirdine, tacrine, rivastigmine, galantamine, memantine, mitazal pyridoxine, venlafaxine, desugarin, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline, or any combination thereof.
本文所使用的术语“治疗有效量”是指足以显示出有意义的患者益处的各活性组分的总量。当使用单独的活性成分单独给药时，该术语仅指该成分。当组合应用时，该术语则是指不论组合、依次或同时给药时，都引起治疗效果的活性成分的组合量。式(I)化合物及其药学上可接受的盐如上所述。从与制剂其他成分相容以及对其接受者无害的意义上来讲，载体、稀释剂或赋形剂必须是可接受的。根据本公开内容的另一方面，还提供用于制备药物制剂的方法，该方法包括将式(I)化合物或其药学上可接受的盐与一种或多种药学上可接受的载体、稀释剂或赋形剂混匀。本发明所使用的术语“药学上可接受的”是指这样的化合物、原料、组合物和/或剂型，它们在合理医学判断的范围内，适用于与患者组织接触而无过度毒性、刺激性、变态反应或与合理的利益/风险比相对称的其他问题和并发症，并有效用于既定用途。As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to exhibit a meaningful patient benefit. When a single active ingredient is used to be administered alone, the term refers to that ingredient only. When used in combination, the term refers to the combined amounts of active ingredients that, whether administered in combination, sequentially or simultaneously, result in a therapeutic effect. The compounds of formula (I) and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to its recipient. According to another aspect of the present disclosure, there is also provided a method for preparing a pharmaceutical formulation, the method comprising diluting a compound of formula (I), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluting agents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation , allergic reactions or other problems and complications commensurate with a reasonable benefit/risk ratio and are effective for the intended use.
通常，本发明的化合物通过用于发挥类似效用的物质的任何常规施用方式以治疗有效量被施用。适宜的剂量范围典型地为每天1-500mg，优选每天1-100mg，最优选每天1-30mg，这取决于多种因素，例如所治疗疾病的严重性、施用对象的年龄和相对健康状况、所用化合物的效力、施用的途径和形式、施用所针对的适应症以及相关医学执业者的偏好和经验。治疗所述疾病领域的普通技术人员无需过多实验依靠个人知识和本申请的公开内容即能确定用于给定疾病的本发明化合物的治疗有效量。Generally, the compounds of the present invention are administered in a therapeutically effective amount by any conventional mode of administration for substances that exert similar utility. Suitable dosage ranges are typically 1-500 mg per day, preferably 1-100 mg per day, most preferably 1-30 mg per day, depending on factors such as the severity of the disease being treated, the age and relative health of the subject, the use The potency of the compound, the route and form of administration, the indication for which it is administered, and the preferences and experience of the relevant medical practitioner. One of ordinary skill in the art of treating such diseases can, without undue experimentation rely on personal knowledge and the disclosure of this application, to determine the therapeutically effective amount of a compound of the present invention for a given disease.
通常，本发明的化合物以药物制剂形式施用，所述的药物制剂包括那些适于口服(包括口腔和舌下)、直肠、鼻、局部、肺、阴道或胃肠外(包括肌内、动脉内、鞘内、皮下和静脉内)施用的药物制剂或适于吸入或吹入施用形式的药物制剂。优选的施用方式通常为口服，使用合适的日剂量方案，可根据疾痛程度对其进行调整。Typically, the compounds of the present invention are administered in the form of pharmaceutical formulations including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial) , intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred mode of administration is usually oral, using an appropriate daily dosage regimen, which can be adjusted according to the degree of affliction.
可将本发明的一种或多种化合物与一种或多种常规辅剂、载体或稀释剂一起置于药物组合物和单位剂量形式中。药物组合物和单位剂量形式可包含常规比例的常规成分，含或不含另外的活性化合物或成分，单位剂量形式可以含有与所应用的计划日剂量范围相称的任何适宜的有效量的活性成分。药物组合物的应用形式可以是固体例如片剂或填充胶囊剂、半固体、粉末、缓释制剂或液体例如溶液剂、混悬剂、乳剂、酏剂或口服使用的填充胶囊剂；或是用于直肠或阴道施用的栓剂形式；或是用于胃肠外使用的无菌注射用溶液形式。因此，每片中含有约1mg活性成分或更宽地，含有约0.01至约100mg活性成分的制剂是适宜的代表性的单位剂量形式。One or more compounds of the present invention can be placed in pharmaceutical compositions and unit dosage forms together with one or more conventional adjuvants, carriers or diluents. Pharmaceutical compositions and unit dosage forms may contain conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and unit dosage forms may contain any suitable effective amount of active ingredient commensurate with the planned daily dosage range to be employed. The pharmaceutical compositions may be in the form of solids such as tablets or filled capsules, semi-solids, powders, sustained release formulations or liquids such as solutions, suspensions, emulsions, elixirs or filled capsules for oral use; in the form of suppositories for rectal or vaginal administration; or as sterile injectable solutions for parenteral use. Thus, formulations containing from about 0.01 to about 100 mg of active ingredient per tablet are suitable representative unit dosage forms.
本发明的化合物可以配制成各种口服施用的剂量形式。药物组合物和剂量形式可以包含本发明的一种或多种化合物或其可药用盐作为活性成分。可药用的载体可以是固体或液体。固体形式的制剂包：散剂、片剂、丸剂、胶囊剂、扁囊剂、栓剂和可分散的颗粒剂。固体载体可以是一种或多种物质，其也可以用作稀释剂、矫味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂或包囊材料。在散剂中，载体通常为研细的固体，其与研细的活性成分形成混合物。在片剂中，活性成分通常与具有必需粘合能力的载体以适宜的比例相混合并压制成所需的形状和大小。散剂和片剂优选含有约1％至约70％的活性化合物。适宜的载体包括但不限于碳酸镁、硬脂酸镁、滑石粉、糖、乳糖、果胶、糊精、淀粉、明胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。The compounds of the present invention can be formulated in various dosage forms for oral administration. Pharmaceutical compositions and dosage forms may contain one or more compounds of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. Pharmaceutically acceptable carriers can be solid or liquid. Solid form formulation packages: powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain from about 1% to about 70% active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low Melting point wax, cocoa butter, etc.
术语“制剂”旨在包括含有包囊材料作为载体以提供胶囊的活性化合物的制剂，在所述胶囊中带有或不带有载体的活性成分被与之结合的该载体所包围。类似地，还包括扁囊剂和锭剂。片剂、散剂、胶囊剂、丸剂、扁囊剂和锭剂均是适于口服施用的固体形式。The term "formulation" is intended to include formulations of the active compound containing an encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without carriers, is surrounded by the carrier in association with it. Similarly, cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets and lozenges are solid forms suitable for oral administration.
其它适于口服施用的形式包括液体形式的制剂(包括乳剂、糖浆、酏剂、水性溶液剂、水性混悬剂)或旨在使用前即刻转变为液体形式制剂的固体形式的制剂。乳剂可以在溶液例如丙二醇水溶液中制备或可以含有乳化剂例如卵磷脂、脱水山梨醇单油酸酯或阿拉伯胶。水性溶液剂可通过将活性成分溶解在水中并加入适宜的着色剂、矫味剂、稳定剂和增稠剂来制备。水性混悬剂可通过用粘性物质例如天然或合成的胶、树脂、甲基纤维素、羧甲基纤维素钠和其它公知的悬浮剂将研细的活性成分分散在水中来制备。液体形式的制剂包括溶液剂、混悬剂和乳剂，除了活性成分外其还可以含有着色剂、矫味剂、稳定剂、缓冲剂、人造的和天然的甜味剂、分散剂、增稠剂、增溶剂等。Other forms suitable for oral administration include liquid form preparations (including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions) or solid form preparations which are intended to be converted shortly before use. Emulsions can be prepared in solutions such as aqueous propylene glycol solutions or can contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active ingredient in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Liquid form preparations include solutions, suspensions and emulsions, which may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners , solubilizer, etc.
本发明的化合物可被配制用于胃肠外施用(例如，通过注射如快速浓注或连续输注施用)并且可以以单位剂量形式存在于安瓿、预先灌装的注射器、小容量输液中或存在于添加了防腐剂的多剂量容器中。组合物可采用的形式有例如在油性或水性赋形剂中的混悬剂、溶液剂或乳剂，例如在聚乙二醇水溶液中的溶液剂。油性或非水性载体、稀释剂、溶剂或赋形剂的例子包括丙二醇、聚乙二醇、植物油(例如橄榄油)和注射用有机酯(例如油酸乙酯)，并且可含有制剂物质如防腐剂、湿润剂、乳化剂或悬浮剂、稳定剂和/或分散剂。或者，活性成分可以为粉末形式，其获得方法是将无菌固体进行无菌分装或通过将溶液冻干以便在使用前用适宜的赋形剂例如无菌、无热原的水进行构建。The compounds of the present invention may be formulated for parenteral administration (eg, by injection such as bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, prefilled syringes, small volume infusions or in the presence of in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycols. Examples of oily or non-aqueous carriers, diluents, solvents, or excipients include propylene glycol, polyethylene glycol, vegetable oils (eg, olive oil), and injectable organic esters (eg, ethyl oleate), and may contain formulation substances such as preservatives agents, wetting agents, emulsifying or suspending agents, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, which can be obtained by aseptic aliquoting of sterile solids or by lyophilizing solutions for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use.
本发明的化合物可被配制用于以软膏剂、乳膏剂或洗剂形式或以透皮贴剂形式局部施用于表皮。软膏剂和乳膏剂可以例如用添加了适宜的增稠剂和/或胶凝剂的水性或油性基质进行配制。洗剂可以用水性或油性基质配制并且通常还含有一种或多种乳化剂、稳定剂、分散剂、悬浮剂、增稠剂或着色剂。适于在口中局部施用的制剂包括包含处于矫味基质、通常为蔗糖和阿拉伯胶或西黄蓍胶中的活性成分的锭剂；包含处于惰性基质如明胶和甘油或蔗糖和阿拉伯胶中的活性成分的锭剂；以及包含处于适宜液体载体中的活性成分的漱口剂。The compounds of the present invention may be formulated for topical application to the epidermis in the form of an ointment, cream or lotion or in the form of a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents. Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; containing the active ingredient in an inert base such as gelatin and glycerol or sucrose and acacia lozenges of the ingredients; and a mouthwash containing the active ingredient in a suitable liquid carrier.
本发明的化合物可被配制用于以栓剂形式施用。可首先将低熔点蜡如脂肪酸甘油酯混合物或可可脂熔化，并将活性成分例如通过搅拌均匀分散。然后将熔融的均匀混合物倒入合适大小的模具中，使其冷却并固化。The compounds of the present invention may be formulated for administration in the form of suppositories. A low-melting wax such as a fatty acid glyceride mixture or cocoa butter can first be melted and the active ingredient dispersed homogeneously, eg by stirring. The molten homogeneous mixture is then poured into appropriately sized molds, allowed to cool and solidify.
本发明的化合物可被配制用于阴道施用。除活性成分外还含有本领域公知载体的阴道栓、卫生栓、乳青剂、凝胶剂、糊剂、泡沫剂或喷雾剂是适宜的。The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient carriers known in the art are suitable.
本发明的化合物可被配制用于经鼻施用。可将溶液剂或混悬剂通过常规方法、例如用滴管、吸管或喷雾器直接应用于鼻腔。制剂可以是单剂量或多剂量形式。对于滴管或吸管的多剂量形式，这可以通过由患者施用适宜的、预定体积的溶液剂或混悬剂来实现。对于喷雾器，这可以例如通过计量雾化喷雾泵来实现。The compounds of the present invention may be formulated for nasal administration. Solutions or suspensions can be applied directly to the nasal cavity by conventional means, eg, with a dropper, pipette, or nebulizer. The formulations may be in single-dose or multiple-dose form. For multiple dose forms with a dropper or pipette, this can be accomplished by the patient administering a suitable, predetermined volume of the solution or suspension. For nebulizers, this can be achieved, for example, by means of a metered atomizing spray pump.
本发明的化合物可被配制用于气雾剂施用，特别是施用于呼吸道并且包括鼻内施用。化合物通常具有小的粒度，例如5微米或更小数量级的粒度。所述的粒度可通过本领域公知的方法、例如通过微粉化获得。活性成分以含有适宜抛射剂如含氯氟烃(CFC)例如二氯二氟甲烷、三氯氟甲烷或二氯四氟乙烷或者二氧化碳或其它适宜气体的加压包装提供。气雾剂还可合适地含有表面活性剂如卵磷脂。药物剂量可通过计量阀控制。或者，活性成分可以以干燥粉末形式、例如在适宜粉末基质如乳糖、淀粉、淀粉衍生物如羟丙基甲基纤维素和聚乙烯吡咯烷酮中的化合物的粉末混合物形式提供。粉末载体将在鼻腔中形成凝胶。粉末组合物可以以单位剂量形式例如以明胶胶囊剂或药筒或泡罩包装形式存在可通过吸入器由其中施用粉末。The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compounds typically have small particle sizes, eg, on the order of 5 microns or less. Said particle size can be obtained by methods known in the art, for example by micronization. The active ingredient is provided in a pressurized pack containing a suitable propellant such as a chlorofluorocarbon (CFC) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Aerosols may also suitably contain surfactants such as lecithin. The dose of the drug can be controlled by a metering valve. Alternatively, the active ingredient may be provided in dry powder form, for example as a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose and polyvinylpyrrolidone. The powder carrier will form a gel in the nasal cavity. Powder compositions may be presented in unit dosage form, eg, in gelatin capsules or cartridges or blister packs, from which the powder may be administered by means of an inhaler.
需要时，制剂可以用适于缓释或控释施用活性成分的肠溶包衣进行制备。例如，本发明的化合物可被配制成透皮或皮下药物递送装置。当必须缓释化合物时和当患者对治疗方案的依从性至关重要时，这些递送系统是有利的。透皮递送系统中的化合物经常附着在皮肤粘着性固体载体上。所关注的化合物也可以与渗透促进剂、例如月桂氮革酮(1-十二烷基氮杂环庚-2-酮)组合使用。可通过手术或注射将缓释递送系统皮下插入到皮下层。皮下植入物将化合物包囊在液体可溶性膜、例如硅橡胶或生物可降解的聚合物例如聚乳酸中。When desired, formulations can be prepared with enteric coatings suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated into transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is critical. Compounds in transdermal delivery systems are often attached to skin-adhesive solid carriers. Compounds of interest can also be used in combination with penetration enhancers, such as lauroazone (1-dodecylazepan-2-one). Sustained release delivery systems can be inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate the compound in a liquid soluble membrane such as silicone rubber or biodegradable polymers such as polylactic acid.
药物制剂优选为单位剂量形式。在该形式中，制剂被细分为含有适宜量活性成分的单位剂量。单位剂量形式可以是成套包装的制剂，包装中含有离散量的制剂，例如成套包装的片剂、胶囊剂和在小瓶中的粉末或安瓶剂。另外，单位剂量形式可以是胶囊剂、片剂、扁囊剂或锭剂本身，或者其可以是成套包装形式中适宜数量的这些形式中的任何一种。The pharmaceutical formulations are preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders or ampoules in vials. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
其它适宜的药用载体和它们的制剂在Remington：The Science and Practice ofPharmacy 1995Martin，E.W编辑，Mack Publishing Company，第19版，Easton，Pennsylvania中有描述。Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995 Martin, E.W ed., Mack Publishing Company, 19th edition, Easton, Pennsylvania.
本发明化合物和药物组合物的用途Use of the Compounds and Pharmaceutical Compositions of the Invention
本发明提供的上述化合物和药物组合物可用于制备预防、治疗或减轻阿尔茨海默症的药品，也可以用于制备预防、治疗或减轻与5-HT6受体有关的疾病的药品。The above compounds and pharmaceutical compositions provided by the present invention can be used to prepare medicines for preventing, treating or alleviating Alzheimer's disease, and can also be used to prepare medicines for preventing, treating or alleviating diseases related to5 -HT6 receptors.
本发明的药物组合物的特征包括式(I)所示的化合物或本发明所列出的化合物，以及药学上可接受的载体，辅剂或赋形剂。本发明的组合物中化合物的量可以有效地可探测地拮抗5-HT6受体以治疗CNS病症，胃肠道疾病和肥胖症，其中所述的CNS病症为ADHD，焦虑，与精神紧张相关的疾病，精神分裂症，强迫观念与行为障碍，躁狂抑郁症，神经病症，记忆障碍，注意力缺陷障碍，帕金森病，肌萎缩性侧索硬化，阿尔茨海默症和亨廷顿舞蹈病，等等。The characteristics of the pharmaceutical composition of the present invention include the compound represented by formula (I) or the compounds listed in the present invention, and a pharmaceutically acceptable carrier, adjuvant or excipient. The amount of the compound in the compositions of the present invention is effective to detectably antagonize the5 -HT6 receptor for the treatment of CNS disorders, gastrointestinal disorders and obesity, wherein said CNS disorders are ADHD, anxiety, stress-related diseases, schizophrenia, obsessive-compulsive disorder, manic-depressive disorder, neurological disorders, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease, and many more.
本发明的化合物或药学上可接受的组合物的“有效量”或“有效剂量”是指处理或减轻一个或多个本发明所提到病症的严重度的有效量。根据本发明的方法，化合物和组合物可以是任何给药量和任何给药途径来有效地用于处理或减轻疾病的严重程度。必需的准确的量将根据患者的情况而改变，这取决于种族，年龄，患者的一般条件，感染的严重程度，特殊的因素，给药方式，等等。化合物或组合物可以和一个或多个其他治疗剂联合给药，如本发明所讨论的。An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present invention refers to an amount effective to treat or lessen the severity of one or more of the disorders referred to herein. According to the methods of the present invention, the compounds and compositions may be administered in any amount and by any route of administration effective for treating or reducing the severity of the disease. The exact amount necessary will vary from patient to patient, depending on race, age, the general condition of the patient, the severity of the infection, particular factors, the mode of administration, and the like. The compound or composition can be administered in combination with one or more other therapeutic agents, as discussed herein.
本发明的化合物及药物组合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物中的哺乳动物。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。In addition to their therapeutic benefits in humans, the compounds and pharmaceutical compositions of the present invention may also be used in veterinary treatment of mammals in pets, introduced species and farm animals. Examples of other animals include horses, dogs and cats. Here, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
本发明化合物的一般合成方法General Synthesis of Compounds of the Invention
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。To illustrate the invention, the following examples are set forth. It is to be understood, however, that the invention is not limited to these examples, but merely provides methods of practicing the invention.
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。In general, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are as defined in formula (I). The following reaction schemes and examples serve to further illustrate the content of the present invention.
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modifying methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如凌凯医药，Aldrich Chemical Company,Inc.,Arco Chemical Company和AlfaChemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Linkchem Pharmaceuticals, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Reagent Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.
无水四氢呋喃是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，N,N-二甲基乙酰胺和石油醚是经无水硫酸钠事先干燥使用。Anhydrous tetrahydrofuran is obtained by refluxing and drying with metallic sodium. Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride. Ethyl acetate, N,N-dimethylacetamide and petroleum ether were previously dried over anhydrous sodium sulfate and used.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。The following reactions are generally carried out under positive nitrogen or argon pressure or a drying tube is set over anhydrous solvent (unless otherwise indicated), the reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dry.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。核磁共振光谱以CDC13、DMSO-d6、CD3OD或丙酮-d6为溶剂(报导以ppm为单位)，用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)，d(doublet，双峰)，t(triplet，三重峰)，m(multiplet，多重峰)，br(broadened，宽峰)，dd(doublet ofdoublets，双二重峰)，dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. NMR spectra were performed with CDC13,DMSO- d6,CD3OD , or acetone- d6 as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened) peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplet). Coupling constant, expressed in Hertz (Hz).
低分辨率质谱(MS)数据通过配备G1312A二元泵和a G1316A TCC(柱温保持在30℃)的Agilent 6320系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315B DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 Series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C), a G1329A autosampler and a G1315B DAD detector applied to For analysis, the ESI source was applied to the LC-MS spectrometer.
低分辨率质谱(MS)数据通过配备G1311A四元泵和G1316A TCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315D DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (MS) data were determined by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30°C), a G1329A autosampler and a G1315D DAD detector for analysis , ESI source applied to LC-MS spectrometer.
以上两种光谱仪都配备了Agilent Zorbax SB-C18柱，规格为2.1×30mm，5μm。注射体积是通过样品浓度来确定；流速为0.6mL/min；HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。流动相为0.1％的甲酸乙腈溶液(相A)和0.1％的甲酸超纯水溶液(相B)。Both of the above spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1 × 30 mm, 5 μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL/min; HPLC peaks were read by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B).
化合物纯化是通过Agilent 1100系列高效液相色谱(HPLC)来评价的，其中UV检测在210nm和254nm处，Zorbax SB-C18柱，规格为2.1×30mm，4μm，10分钟，流速为0.6mL/min，5-95％的(0.1％甲酸乙腈溶液)的(0.1％甲酸水溶液)，柱温保持在40℃。Compound purification was assessed by Agilent 1100 series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm, Zorbax SB-C18 column, 2.1 x 30 mm, 4 μm, 10 min, flow rate 0.6 mL/min , 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), and the column temperature was kept at 40°C.
下面简写词的使用贯穿本发明：The following abbreviations are used throughout this disclosure:
Pd/C 钯炭催化剂Pd/C Palladium Carbon Catalyst
AcOH 醋酸AcOH acetic acid
MeCN,CH3CN 乙腈MeCN, CH3 CN Acetonitrile
CHCl3 氯仿CHCl3 chloroform
CDC13 氘代氯仿CDC13 deuterochloroform
DMSO 二甲基亚砜DMSO Dimethyl sulfoxide
DMSO-d6 氘代二甲基亚砜DMSO-d6 -deuterated dimethyl sulfoxide
DMF N,N-二甲基甲酰胺DMF N,N-Dimethylformamide
EtOAc,EA 乙酸乙酯EtOAc, EA Ethyl acetate
HCl 盐酸HCl hydrochloric acid
MgSO4 硫酸镁MgSO4 Magnesium Sulfate
MgCl2 氯化镁MgCl2 Magnesium Chloride
MeOH,CH3OH 甲醇MeOH, CH3 OH methanol
HCHO 甲醛HCHO formaldehyde
CH2Cl2,DCM 二氯甲烷CH2 Cl2 , DCM Dichloromethane
mL,ml 毫升mL,ml milliliter
PE 石油醚(60-90℃)PE petroleum ether (60-90℃)
Na2CO3 碳酸钠Na2 CO3 Sodium Carbonate
NaHCO3 碳酸氢钠NaHCO3 Sodium Bicarbonate
M,mol/L 摩尔/升M,mol/L mol/L
K2CO3 碳酸钾K2 CO3 Potassium Carbonate
KOH 氢氧化钾KOH Potassium Hydroxide
RT 室温RT room temperature
Rt 保留时间Rt retention time
h,hr 小时h,hr hours
NaBH3CN 氰基硼氢化钠NaBH3 CN Sodium cyanoborohydride
NaCl 氯化钠NaCl Sodium Chloride
KCl 氯化钾KCl Potassium Chloride
Na2SO4 硫酸钠Na2 SO4 Sodium Sulfate
THF 四氢呋喃THF tetrahydrofuran
EDTA 乙二胺四乙酸EDTA Ethylenediaminetetraacetic acid
PEI 聚乙烯亚胺PEI Polyethyleneimine
Pargyline 帕吉林Pargyline
Tris-HCl 三(羟甲基)氨基甲烷-盐酸Tris-HCl Tris(hydroxymethyl)aminomethane-hydrochloric acid
NADPH 还原型辅酶IINADPH reduced coenzyme II
下列合成方案描述了制备本发明公开化合物的步骤。除非另外说明，
合成方案1Synthesis Scheme 1
式(5)所示的化合物可以通过合成方案1所描述的方法制备得到。首先，式(1)所示的化合物在碱的作用下与哌啶酮衍生物反应，得到式(2)所示的产物；然后式(2)所示的化合物脱除保护基得到式(3)所示的化合物；式(3)所示的化合物与式(4)所示的化合物反应，还原胺化后得到式(5)所示的目标化合物。The compound represented by formula (5 ) can be prepared by the method described in Synthesis Scheme 1. First, the compound represented by the formula (1 ) reacts with a piperidone derivative under the action of a base to obtain the product represented by the formula (2 ); then the compound represented by the formula (2 ) is deprotected to obtain the formula (3) The compound represented by ); the compound represented by the formula (3 ) reacts with the compound represented by the formula (4 ), and the target compound represented by the formula (5 ) is obtained after reductive amination.
以下结合实施例对本发明提供的化合物、药物组合物及其应用进行进一步说明。The compounds, pharmaceutical compositions and applications provided by the present invention will be further described below with reference to the examples.
实施例Example
实施例1 3-(1-(3-(2,2,2-三氟乙氧基)苄基)哌啶-4-基)-1H-吲哚的合成Example 1 Synthesis of 3-(1-(3-(2,2,2-trifluoroethoxy)benzyl)piperidin-4-yl)-1H-indole
步骤1)4-(1H-吲哚-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成Step 1) Synthesis of 4-(1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester
将吲哚(5.0g,42.7mmol)和4-氧代哌啶-1-羧酸叔丁酯(10.1g,51.2mmol)加入到甲醇(50mL)中，然后加入KOH(4.78g,85.4mmol)，在油浴70℃下反应8小时后停止反应，加入水(150mL)淬灭，析出大量黄色固体，过滤，滤渣真空干燥即得到标题化合物为棕黄色固体(10.9g,86.2％)。Indole (5.0 g, 42.7 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (10.1 g, 51.2 mmol) were added to methanol (50 mL) followed by KOH (4.78 g, 85.4 mmol) , the reaction was stopped after 8 hours at 70°C in an oil bath, water (150 mL) was added to quench, a large amount of yellow solid was precipitated, filtered, and the filter residue was vacuum-dried to obtain the title compound as a brownish yellow solid (10.9 g, 86.2%).
MS(ESI,pos.ion)m/z:299.2[M+H]+；MS(ESI, pos.ion) m/z: 299.2 [M+H]+ ;
1H NMR(400MHz,CDCl3)δ(ppm):8.43(s,1H),7.74(d,J＝8.2Hz,1H),7.31(d,J＝8.2Hz,1H),7.18–7.15(m,1H),7.08–7.05(m,1H),6.94(d,J＝2.4Hz,1H),6.08(brs,1H),4.12(d,J＝2.0Hz,2H),3.65(t,J＝5.6Hz,2H),2.53(brs,2H),1.49(s,9H).1 H NMR (400 MHz, CDCl3 ) δ (ppm): 8.43 (s, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.18-7.15 (m ,1H),7.08–7.05(m,1H),6.94(d,J=2.4Hz,1H),6.08(brs,1H),4.12(d,J=2.0Hz,2H),3.65(t,J= 5.6Hz, 2H), 2.53(brs, 2H), 1.49(s, 9H).
步骤2)4-(1H-吲哚-3-基)哌啶-1-羧酸叔丁酯的合成Step 2) Synthesis of 4-(1H-indol-3-yl)piperidine-1-carboxylate tert-butyl ester
将4-(1H-吲哚-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯(10.0g,33.5mmol)加入到甲醇(30mL)和四氢呋喃(30mL)的混合溶剂中，然后加入Pd/C(3.0g,10％)。在25℃下1atmH2压力下反应15小时。停止反应，过滤，滤液减压旋干，柱层析纯化(石油醚/乙酸乙酯(v/v)＝10/1)得到标题化合物为白色固体(9.14g,91％)。4-(1H-Indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (10.0 g, 33.5 mmol) was added to methanol (30 mL) and tetrahydrofuran (30 mL) , and then added Pd/C (3.0 g, 10%). The reaction was carried out at 25°C under1 atmH2 pressure for 15 hours. The reaction was stopped, filtered, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=10/1) to obtain the title compound as a white solid (9.14 g, 91%).
MS(ESI,pos.ion)m/z:201.1[M+H-100]+；MS(ESI, pos.ion) m/z: 201.1[M+H-100]+ ;
1H NMR(400MHz,CDCl3)δ(ppm):8.24(s,1H),7.82(d,J＝8.4Hz,1H),7.35(d,J＝7.8Hz,1H),7.24–7.21(m,1H),7.19–7.16(m,1H),7.09(d,J＝3.0Hz,1H),4.22(t,J＝9.2Hz,2H),2.95–2.84(m,3H),2.03–1.98(m,2H),1.68–1.54(m,2H),1.47(s,9H).1 H NMR (400 MHz, CDCl3 ) δ (ppm): 8.24 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.24-7.21 (m ,1H),7.19–7.16(m,1H),7.09(d,J=3.0Hz,1H),4.22(t,J=9.2Hz,2H),2.95–2.84(m,3H),2.03–1.98( m, 2H), 1.68–1.54 (m, 2H), 1.47 (s, 9H).
步骤3)3-(哌啶-4-基)-1H-吲哚的合成Step 3) Synthesis of 3-(piperidin-4-yl)-1H-indole
在25℃下将4-(1H-吲哚-3-基)哌啶-1-羧酸叔丁酯(9.0g,30mmol)加入到二氯甲烷(50mL)中，然后加入氯化氢的乙酸乙酯溶液(20mL,2mmol/mL)，搅拌反应3小时后停止反应，加入饱和碳酸氢钠溶液淬灭(50mL)，分液后有机相用无水硫酸钠干燥。过滤，滤液减压旋干，柱层析纯化(二氯甲烷/甲醇(v/v)＝10/1)得到标题化合物为淡黄色油状物(5.46g,91％)。4-(1H-Indol-3-yl)piperidine-1-carboxylate tert-butyl ester (9.0 g, 30 mmol) was added to dichloromethane (50 mL) at 25°C followed by hydrogen chloride in ethyl acetate The solution (20 mL, 2 mmol/mL) was stirred for 3 hours to stop the reaction, and saturated sodium bicarbonate solution was added to quench (50 mL), and the organic phase was dried with anhydrous sodium sulfate after separation. After filtration, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v)=10/1) to obtain the title compound as a pale yellow oil (5.46 g, 91%).
MS(ESI,pos.ion)m/z:201.1[M+H]+；MS(ESI, pos.ion) m/z: 201.1[M+H]+ ;
1H NMR(400MHz,DMSO-d6)δ(ppm):8.47(s,1H),7.75(d,J＝8.4Hz,1H),7.32(d,J＝8.4Hz,1H),7.17–7.14(m,1H),7.09–7.04(m,1H),6.93(d,J＝2.4Hz,1H),3.37(brs,2H),3.07–2.99(m,3H),2.06–2.04(m,2H),2.02–1.90(m,2H).1 H NMR (400 MHz, DMSO-d6 ) δ (ppm): 8.47 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.17-7.14 (m, 1H), 7.09–7.04 (m, 1H), 6.93 (d, J=2.4Hz, 1H), 3.37 (brs, 2H), 3.07–2.99 (m, 3H), 2.06–2.04 (m, 2H) ), 2.02–1.90 (m, 2H).
步骤4)3-(1-(3-(2,2,2-三氟乙氧基)苄基)哌啶-4-基)-1H-吲哚的合成Step 4) Synthesis of 3-(1-(3-(2,2,2-trifluoroethoxy)benzyl)piperidin-4-yl)-1H-indole
在25℃下将3-(哌啶-4-基)-1H-吲哚(300mg,1.5mmol)，3-(2,2,2-三氟乙氧基)苯甲醛(408mg,2.0mmol)和AcOH(0.2mL)加入到MeOH(10mL)中，然后加入NaBH3CN(284mg,4.5mmol)，反应5小时后停止反应，依次加入水(10mL)和碳酸钠(318mg,3.0mmol)淬灭反应。用二氯甲烷(50mL x 3)萃取，合并有机相，用无水硫酸钠干燥。过滤，滤液减压旋干，柱层析纯化(二氯甲烷/甲醇(v/v)＝50/1)得到标题化合物为淡黄色油状物(326mg,56％)。3-(piperidin-4-yl)-1H-indole (300 mg, 1.5 mmol), 3-(2,2,2-trifluoroethoxy)benzaldehyde (408 mg, 2.0 mmol) at 25°C and AcOH (0.2 mL) were added to MeOH (10 mL), then NaBH3 CN (284 mg, 4.5 mmol) was added, the reaction was stopped after 5 hours, and water (10 mL) and sodium carbonate (318 mg, 3.0 mmol) were added to quench reaction. Extract with dichloromethane (50 mL x 3), combine the organic phases and dry over anhydrous sodium sulfate. Filtration, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v)=50/1) to obtain the title compound as a pale yellow oil (326 mg, 56%).
MS(ESI,pos.ion)m/z:389.1[M+H]+；MS(ESI, pos.ion) m/z: 389.1 [M+H]+ ;
1H NMR(600MHz,CDCl3)δ(ppm):8.05(s,1H),7.67(d,J＝7.6Hz,1H),7.33(d,J＝8.2Hz,1H),7.17(t,J＝7.8Hz,2H),7.04(t,J＝8.0Hz,1H),6.98(d,J＝2.4Hz,1H),6.83(d,J＝7.8Hz,1H),6.76(dd,J＝8.2,2.4Hz,1H),6.68(s,1H),4.34(q,J＝8.4Hz,2H),3.56(s,2H),2.98(t,J＝11.4Hz,2H),2.81–2.75(m,1H),2.17(t,J＝11.4Hz,2H),2.06–2.01(m,2H),1.85–1.78(m,2H).1 H NMR (600 MHz, CDCl3 ) δ (ppm): 8.05 (s, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.17 (t, J =7.8Hz,2H),7.04(t,J=8.0Hz,1H),6.98(d,J=2.4Hz,1H),6.83(d,J=7.8Hz,1H),6.76(dd,J=8.2 ,2.4Hz,1H),6.68(s,1H),4.34(q,J=8.4Hz,2H),3.56(s,2H),2.98(t,J=11.4Hz,2H),2.81–2.75(m ,1H),2.17(t,J＝11.4Hz,2H),2.06–2.01(m,2H),1.85–1.78(m,2H).
实施例2 3-(1-(3-(2,2,3,3-四氟丙氧基)苄基)哌啶-4-基)-1H-吲哚的合成Example 2 Synthesis of 3-(1-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)piperidin-4-yl)-1H-indole
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将3-(哌啶-4-基)-1H-吲哚(300mg,1.5mmol)，3-(2,2,3,3-四氟丙氧基)苯甲醛(472mg,2.0mmol)和NaBH3CN(284mg,4.5mmol)在MeOH(10mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(322mg,51.0％)。The title compound in this step was prepared according to the method described in step 4 of Example 1, namely 3-(piperidin-4-yl)-1H-indole (300 mg, 1.5 mmol), 3-(2,2,3,3 - Tetrafluoropropoxy)benzaldehyde (472 mg, 2.0 mmol) and NaBH3 CN (284 mg, 4.5 mmol) were prepared by reaction in MeOH (10 mL), and the crude product was subjected to silica gel column chromatography (dichloromethane/methanol (v/ v)=50/1) Purification, concentration and drying to give the title compound as a pale yellow oil (322 mg, 51.0%).
MS(ESI,pos.ion)m/z:421.1[M+H]+；MS(ESI, pos.ion) m/z: 421.1[M+H]+ ;
1H NMR(600MHz,CDCl3)δ(ppm):8.04(s,1H),7.69(d,J＝8.4Hz,1H),7.34(d,J＝8.4Hz,1H),7.17(td,J＝7.4,3.6Hz,2H),7.05–7.02(m,1H),6.98(d,J＝2.4Hz,1H),6.82(d,J＝7.2Hz,1H),6.74(dd,J＝8.4,2.4Hz,1H),6.68(s,1H),6.06(tt,J＝52.8,4.8Hz,1H),4.36(t,J＝12.0Hz,2H),3.55(s,2H),3.00(t,J＝11.4Hz,2H),2.83–2.74(m,1H),2.17(t,J＝11.4Hz,2H),2.06–2.02(m,2H),1.89–1.74(m,2H).1 H NMR (600 MHz, CDCl3 ) δ (ppm): 8.04 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.17 (td, J =7.4,3.6Hz,2H),7.05–7.02(m,1H),6.98(d,J=2.4Hz,1H),6.82(d,J=7.2Hz,1H),6.74(dd,J=8.4, 2.4Hz, 1H), 6.68(s, 1H), 6.06(tt, J=52.8, 4.8Hz, 1H), 4.36(t, J=12.0Hz, 2H), 3.55(s, 2H), 3.00(t, J=11.4Hz, 2H), 2.83–2.74 (m, 1H), 2.17 (t, J=11.4Hz, 2H), 2.06–2.02 (m, 2H), 1.89–1.74 (m, 2H).
实施例3 5-甲氧基-3-(1-(3-(2,2,2-三氟乙氧基)苄基)哌啶-4-基)-1H-吲哚的Example 3 5-methoxy-3-(1-(3-(2,2,2-trifluoroethoxy)benzyl)piperidin-4-yl)-1H-indole合成synthesis
步骤1)4-(5-甲氧基-1H-吲哚-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成Step 1) Synthesis of 4-(5-methoxy-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
本步骤标题化合物参照实施例1步骤1所描述的方法制备得到，即将5-甲氧基吲哚(5.0g,34.0mmol)、4-氧代哌啶-1-羧酸叔丁酯(8.1g,41.0mmol)和氢氧化钾(3.8g,68.0mmol)在甲醇(50mL)中反应制备，过滤干燥得到标题化合物为棕色固体(10.3g,92.3％)。The title compound in this step was prepared according to the method described in step 1 of Example 1, namely 5-methoxyindole (5.0 g, 34.0 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (8.1 g) , 41.0 mmol) and potassium hydroxide (3.8 g, 68.0 mmol) in methanol (50 mL), filtered and dried to give the title compound as a brown solid (10.3 g, 92.3%).
MS(ESI,pos.ion)m/z:329.1[M+H]+；MS(ESI, pos.ion) m/z: 329.1[M+H]+ ;
1H NMR(400MHz,CDCl3)δ(ppm):8.27(s,1H),7.29(d,J＝2.4Hz,1H),7.24(d,J＝8.8Hz,1H),7.12(d,J＝2.4Hz,1H),6.86(dd,J＝8.8,2.4Hz,1H),6.08(s,1H),4.12(d,J＝2.0Hz,2H),3.85(s,3H),3.65(t,J＝5.6Hz,2H),2.53(brs,2H),1.49(s,9H).1 H NMR (400 MHz, CDCl3 ) δ (ppm): 8.27 (s, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 7.12 (d, J ＝2.4Hz,1H),6.86(dd,J＝8.8,2.4Hz,1H),6.08(s,1H),4.12(d,J＝2.0Hz,2H),3.85(s,3H),3.65(t , J=5.6Hz, 2H), 2.53(brs, 2H), 1.49(s, 9H).
步骤2)4-(5-甲氧基-1H-吲哚-3-基)哌啶-1-羧酸叔丁酯的合成Step 2) Synthesis of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid tert-butyl ester
本步骤标题化合物参照实施例1步骤2所描述的方法制备得到，即将4-(5-甲氧基-1H-吲哚-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁基酯(10.0g,30.5mmol)和Pd/C(3.0g,10％)在THF(30mL)和MeOH(20mL)的混合溶剂中反应制备，粗产物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝10/1)纯化，浓缩干燥得到标题化合物为白色固体(8.6g,85.0％)。The title compound in this step was prepared according to the method described in Example 1, Step 2, namely 4-(5-methoxy-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)- Carboxylic acid tert-butyl ester (10.0 g, 30.5 mmol) and Pd/C (3.0 g, 10%) were prepared by reacting in a mixed solvent of THF (30 mL) and MeOH (20 mL). The crude product was subjected to silica gel column chromatography (petroleum Ether/ethyl acetate (v/v)=10/1) was purified and concentrated to dryness to give the title compound as a white solid (8.6 g, 85.0%).
MS(ESI,pos.ion)m/z:231.3[M+H-100]+；MS(ESI, pos.ion) m/z: 231.3 [M+H-100]+ ;
1H NMR(400MHz,CDCl3)δ(ppm):7.95(s,1H),7.23(d,J＝8.8Hz,1H),7.03(d,J＝2.0Hz,1H),6.91(d,J＝2.0Hz,1H),6.84(dd,J＝8.8,2.4Hz,1H),4.22(t,J＝9.2Hz,2H),3.85(s,3H),2.95–2.84(m,3H),2.03–2.00(m,2H),1.68–1.54(m,2H),1.47(s,9H).1 H NMR (400 MHz, CDCl3 ) δ (ppm): 7.95 (s, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.91 (d, J ＝2.0Hz,1H),6.84(dd,J＝8.8,2.4Hz,1H),4.22(t,J＝9.2Hz,2H),3.85(s,3H),2.95–2.84(m,3H),2.03 –2.00(m,2H),1.68–1.54(m,2H),1.47(s,9H).
步骤3)5-甲氧基-3-(哌啶-4-基)-1H-吲哚的合成Step 3) Synthesis of 5-methoxy-3-(piperidin-4-yl)-1H-indole
本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将4-(5-甲氧基-1H-吲哚-3-基)哌啶-1-羧酸叔丁酯(8.6g,26.0mmol)和氯化氢的乙酸乙酯溶液(20mL,2mmol/mL)在二氯甲烷(50mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝30/1)纯化，浓缩干燥得到标题化合物为淡黄色固体(4.86g,81.0％)。The title compound in this step was prepared according to the method described in step 3 of Example 1, namely tert-butyl 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylate (8.6 g, 26.0 mmol) and hydrogen chloride solution in ethyl acetate (20 mL, 2 mmol/mL) were prepared by reacting in dichloromethane (50 mL), and the crude product was subjected to silica gel column chromatography (dichloromethane/methanol (v/v)=30/1 ), and concentrated to dryness to give the title compound as a pale yellow solid (4.86 g, 81.0%).
MS(ESI,pos.ion)m/z:231.1[M+H]+；MS(ESI, pos.ion) m/z: 231.1[M+H]+ ;
1H NMR(400MHz,DMSO-d6)δ(ppm):10.72(s,1H),7.23(d,J＝8.8Hz,1H),7.13(d,J＝2.4Hz,1H),7.07(d,J＝2.0Hz,1H),6.72(dd,J＝8.8,2.4Hz,1H),3.77(s,3H),3.35(brs,2H),3.06–2.99(m,3H),2.05–2.02(m,2H),2.01–1.90(m,2H).1 H NMR (400 MHz, DMSO-d6 ) δ (ppm): 10.72 (s, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.07 (d , J=2.0Hz, 1H), 6.72(dd, J=8.8, 2.4Hz, 1H), 3.77(s, 3H), 3.35(brs, 2H), 3.06–2.99(m, 3H), 2.05–2.02( m,2H),2.01–1.90(m,2H).
步骤4)5-甲氧基-3-(1-(3-(2,2,2-三氟乙氧基)苄基)哌啶-4-基)-1H-吲哚的合Step 4) Synthesis of 5-methoxy-3-(1-(3-(2,2,2-trifluoroethoxy)benzyl)piperidin-4-yl)-1H-indole成to make
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将5-甲氧基-3-(哌啶-4-基)-1H-吲哚(310mg,1.35mmol)，3-(2,2,2-三氟乙氧基)苯甲醛(450mg,2.20mmol)和NaBH3CN(180mg,1.70mmol)在MeOH(10mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(138mg,24.5％)。The title compound in this step was prepared according to the method described in Example 1, Step 4, namely 5-methoxy-3-(piperidin-4-yl)-1H-indole (310 mg, 1.35 mmol), 3-(2 , 2,2-Trifluoroethoxy)benzaldehyde (450mg, 2.20mmol) andNaBH3CN (180mg, 1.70mmol) were prepared by reaction in MeOH (10mL), and the crude product was subjected to silica gel column chromatography (dichloromethane/ Purified with methanol (v/v)=50/1), concentrated and dried to give the title compound as a pale yellow oil (138 mg, 24.5%).
MS(ESI,pos.ion)m/z:419.3[M+H]+；MS(ESI, pos.ion) m/z: 419.3 [M+H]+ ;
1H NMR(600MHz,CDCl3)δ(ppm):7.86(s,1H),7.26(d,J＝7.8Hz,1H),7.22(d,J＝9.0Hz,1H),7.05(d,J＝1.8Hz,1H),7.02(d,J＝7.2Hz,1H),6.99(s,1H),6.94(d,J＝1.8Hz,1H),6.85–6.79(m,2H),4.34(q,J＝8.4Hz,2H),3.85(s,3H),3.54(s,2H),2.99(t,J＝11.4Hz,2H),2.81–2.73(m,1H),2.17(t,J＝11.4Hz,2H),2.04–2.01(m,2H),1.84–1.75(m,2H)；1 H NMR (600 MHz, CDCl3 ) δ (ppm): 7.86 (s, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.22 (d, J=9.0 Hz, 1H), 7.05 (d, J =1.8Hz,1H),7.02(d,J=7.2Hz,1H),6.99(s,1H),6.94(d,J=1.8Hz,1H),6.85–6.79(m,2H),4.34(q , J=8.4Hz, 2H), 3.85(s, 3H), 3.54(s, 2H), 2.99(t, J=11.4Hz, 2H), 2.81–2.73(m, 1H), 2.17(t, J= 11.4Hz, 2H), 2.04–2.01 (m, 2H), 1.84–1.75 (m, 2H);
13C NMR(150MHz,CDCl3)δ(ppm):157.7,154.0,141.0,131.8,129.6,127.3,124.6(q,J＝276.5Hz),123.5,121.5,120.7,115.7,113.7,112.2,112.0,101.4,66.0(q,J＝35.4Hz),63.5,56.3,54.6,33.6,33.1.13 C NMR (150 MHz, CDCl3 ) δ (ppm): 157.7, 154.0, 141.0, 131.8, 129.6, 127.3, 124.6 (q, J=276.5 Hz), 123.5, 121.5, 120.7, 115.7, 113.7, 112.2, 112.0, 101.4, 66.0 (q, J=35.4Hz), 63.5, 56.3, 54.6, 33.6, 33.1.
实施例4 5-甲氧基-3-(1-(3-(2,2,3,3-四氟丙氧基)苄基)哌啶-4-基)-1H-吲哚Example 4 5-Methoxy-3-(1-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)piperidin-4-yl)-1H-indole的合成Synthesis
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将5-甲氧基-3-(哌啶-4-基)-1H-吲哚(300mg,1.30mmol)，3-(2,2,3,3-四氟丙氧基)苯甲醛(472mg,2.0mmol)和NaBH3CN(246mg,3.9mmol)在MeOH(10mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(235mg,38.8％)。The title compound in this step was prepared according to the method described in Example 1, Step 4, namely 5-methoxy-3-(piperidin-4-yl)-1H-indole (300 mg, 1.30 mmol), 3-(2 , 2,3,3-tetrafluoropropoxy)benzaldehyde (472 mg, 2.0 mmol) and NaBH3 CN (246 mg, 3.9 mmol) were prepared by reaction in MeOH (10 mL), and the crude product was subjected to silica gel column chromatography (dichloromethane). Methane/methanol (v/v)=50/1) was purified, concentrated and dried to give the title compound as a pale yellow oil (235 mg, 38.8%).
MS(ESI,pos.ion)m/z:451.3[M+H]+；MS(ESI, pos.ion) m/z: 451.3[M+H]+ ;
1H NMR(600MHz,CDCl3)δ(ppm):7.86(s,1H),7.26(d,J＝7.8Hz,1H),7.23(d,J＝9.0Hz,1H),7.04(d,J＝1.8Hz,1H),7.02(d,J＝7.2Hz,1H),6.97(s,1H),6.94(d,J＝1.8Hz,1H),6.83(dd,J＝9.0,2.4Hz,1H),6.81(dd,J＝8.4,2.4Hz,1H),6.07(tt,J＝52.8,4.8Hz,2H),4.34(t,J＝12.0Hz,3H),3.85(s,3H),3.55(s,2H),3.00(t,J＝11.4Hz,2H),2.82–2.73(m,1H),2.17(t,J＝11.4Hz,2H),2.04–2.01(m,2H),1.88–1.75(m,2H)；1 H NMR (600 MHz, CDCl3 ) δ (ppm): 7.86 (s, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 7.04 (d, J ＝1.8Hz,1H),7.02(d,J＝7.2Hz,1H),6.97(s,1H),6.94(d,J＝1.8Hz,1H),6.83(dd,J＝9.0,2.4Hz,1H) ),6.81(dd,J＝8.4,2.4Hz,1H),6.07(tt,J＝52.8,4.8Hz,2H),4.34(t,J＝12.0Hz,3H),3.85(s,3H),3.55 (s, 2H), 3.00 (t, J=11.4Hz, 2H), 2.82–2.73 (m, 1H), 2.17 (t, J=11.4Hz, 2H), 2.04–2.01 (m, 2H), 1.88– 1.75(m, 2H);
13C NMR(150MHz,CDCl3)δ(ppm):157.6,154.0,131.8,130.1,129.6,127.3,123.5,121.4,120.8,115.5,114.8(tt,J＝248.4,26.4Hz),113.4,112.2,112.1,109.2(tt,J＝248.4,33.9Hz),101.4,65.4(q,J＝29.9Hz),63.5,56.3,54.6,33.6,33.1.13 C NMR (150 MHz, CDCl3 ) δ (ppm): 157.6, 154.0, 131.8, 130.1, 129.6, 127.3, 123.5, 121.4, 120.8, 115.5, 114.8 (tt, J=248.4, 26.4 Hz), 113.4, 112.2, 112.1, 109.2 (tt, J=248.4, 33.9Hz), 101.4, 65.4 (q, J=29.9Hz), 63.5, 56.3, 54.6, 33.6, 33.1.
实施例5 5-氟-3-(1-(3-(2,2,2-三氟乙氧基)苄基)哌啶-4-基)-1H-吲哚的合成Example 5 Synthesis of 5-fluoro-3-(1-(3-(2,2,2-trifluoroethoxy)benzyl)piperidin-4-yl)-1H-indole
步骤1)4-(5-氟-1H-吲哚-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成Step 1) Synthesis of 4-(5-fluoro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester
本步骤标题化合物参照实施例1步骤1所描述的方法制备得到，即将5-氟吲哚(5.0g,37.0mmol)、4-氧代哌啶-1-羧酸叔丁酯(8.1g,41.0mmol)和氢氧化钾(4.14g,74.0mmol)在甲醇(50mL)中反应制备，过滤干燥得到标题化合物为黄色固体(9.47g,81％)。The title compound in this step was prepared according to the method described in step 1 of Example 1, namely 5-fluoroindole (5.0 g, 37.0 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (8.1 g, 41.0 mmol) mmol) and potassium hydroxide (4.14 g, 74.0 mmol) in methanol (50 mL), which was filtered and dried to give the title compound as a yellow solid (9.47 g, 81%).
MS(ESI,pos.ion)m/z:317.1[M+H]+；MS(ESI, pos.ion) m/z: 317.1 [M+H]+ ;
1H NMR(400MHz,CDCl3)δ(ppm):8.17(s,1H),7.26–7.21(m,2H),7.08(d,J＝2.4Hz,1H),6.93(td,J＝8.6,2.4Hz,1H),6.12(brs,1H),4.11(d,J＝2.0Hz,2H),3.66(t,J＝5.6Hz,2H),2.54(brs,2H),1.49(s,9H).1 H NMR (400 MHz, CDCl3 ) δ (ppm): 8.17 (s, 1H), 7.26-7.21 (m, 2H), 7.08 (d, J=2.4 Hz, 1H), 6.93 (td, J=8.6, 2.4Hz, 1H), 6.12 (brs, 1H), 4.11 (d, J=2.0Hz, 2H), 3.66 (t, J=5.6Hz, 2H), 2.54 (brs, 2H), 1.49 (s, 9H) .
步骤2)4-(5-氟-1H-吲哚-3-基)哌啶-1-羧酸叔丁酯的合成Step 2) Synthesis of tert-butyl 4-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylate
本步骤标题化合物参照实施例1步骤2所描述的方法制备得到，即将4-(5-氟-1H-吲哚-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯(9.0g,28.5mmol)和Pd/C(3.0g,10％)在THF(30mL)和MeOH(20mL)的混合溶剂中反应制备，粗产物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝10/1)纯化，浓缩干燥得到标题化合物为白色固体(7.9g,87.2％)。The title compound in this step was prepared according to the method described in Example 1, Step 2, namely 4-(5-fluoro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-Butyl ester (9.0 g, 28.5 mmol) and Pd/C (3.0 g, 10%) were prepared by reacting in a mixed solvent of THF (30 mL) and MeOH (20 mL), and the crude product was subjected to silica gel column chromatography (petroleum ether/acetic acid) Ethyl ester (v/v)=10/1) was purified, concentrated and dried to give the title compound as a white solid (7.9 g, 87.2%).
1H NMR(400MHz,CDCl3)δ(ppm):8.15(s,1H),7.26–7.22(m,2H),7.09(d,J＝2.4Hz,1H),6.94–6.92(m,1H),4.09–4.02(m,2H),2.99–2.88(m,2H),2.86(brs,1H),1.94-1.91(m,2H),1.53–1.46(m,2H),1.41(s,9H).1 H NMR (400 MHz, CDCl3 ) δ (ppm): 8.15 (s, 1H), 7.26-7.22 (m, 2H), 7.09 (d, J=2.4 Hz, 1H), 6.94-6.92 (m, 1H) ,4.09–4.02(m,2H),2.99–2.88(m,2H),2.86(brs,1H),1.94-1.91(m,2H),1.53–1.46(m,2H),1.41(s,9H) .
步骤3)5-氟-3-(哌啶-4-基)-1H-吲哚的合成Step 3) Synthesis of 5-fluoro-3-(piperidin-4-yl)-1H-indole
本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将4-(5-氟-1H-吲哚-3-基)哌啶-1-羧酸叔丁酯(7.0g,22.0mmol)和氯化氢的乙酸乙酯溶液(20mL,2mmol/mL)在二氯甲烷(50mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝30/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(4.56g,95％)。The title compound of this step was prepared according to the method described in step 3 of Example 1, namely tert-butyl 4-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylate (7.0 g, 22.0 mmol ) and ethyl acetate solution of hydrogen chloride (20 mL, 2 mmol/mL) in dichloromethane (50 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) , concentrated and dried to give the title compound as a pale yellow oil (4.56 g, 95%).
MS(ESI,pos.ion)m/z:219.1[M+H]+；MS(ESI, pos.ion) m/z: 219.1[M+H]+ ;
1H NMR(400MHz,CDCl3)δ(ppm):8.19(s,1H),7.26–7.22(m,2H),7.09(d,J＝2.4Hz,1H),6.93(td,J＝8.4,2.4Hz,1H),3.04–3.02(m,2H),2.80(tt,J＝12.0,3.0Hz,1H),2.65–2.59(m,2H),1.86–1.80(m,2H),1.53(qd,J＝12.0,3.6Hz,2H).1 H NMR (400 MHz, CDCl3 ) δ (ppm): 8.19 (s, 1H), 7.26-7.22 (m, 2H), 7.09 (d, J=2.4 Hz, 1H), 6.93 (td, J=8.4, 2.4Hz, 1H), 3.04–3.02 (m, 2H), 2.80 (tt, J=12.0, 3.0Hz, 1H), 2.65–2.59 (m, 2H), 1.86–1.80 (m, 2H), 1.53 (qd ,J=12.0,3.6Hz,2H).
步骤4)5-氟-3-(1-(3-(2,2,2-三氟乙氧基)苄基)哌啶-4-基)-1H-吲哚的合成Step 4) Synthesis of 5-fluoro-3-(1-(3-(2,2,2-trifluoroethoxy)benzyl)piperidin-4-yl)-1H-indole
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将5-氟-3-(哌啶-4-基)-1H-吲哚(300mg,1.37mmol)，3-(2,2,2-三氟乙氧基)苯甲醛(450mg,2.20mmol)和NaBH3CN(180mg,2.86mmol)在MeOH(10mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(251mg,45％)。The title compound in this step was prepared according to the method described in step 4 of Example 1, namely 5-fluoro-3-(piperidin-4-yl)-1H-indole (300 mg, 1.37 mmol), 3-(2,2 , 2-Trifluoroethoxy)benzaldehyde (450 mg, 2.20 mmol) and NaBH3 CN (180 mg, 2.86 mmol) were prepared by reaction in MeOH (10 mL), and the crude product was subjected to silica gel column chromatography (dichloromethane/methanol ( v/v)=50/1) Purification, concentration and drying to give the title compound as a pale yellow oil (251 mg, 45%).
MS(ESI,pos.ion)m/z:407.1[M+H]+；MS(ESI, pos.ion) m/z: 407.1[M+H]+ ;
1H NMR(600MHz,CDCl3)δ(ppm):8.07(s,1H),7.51(dd,J＝8.2,5.4Hz,1H),7.28–7.25(m,1H),7.03–6.98(m,3H),6.92(d,J＝1.8Hz,1H),6.86–6.82(m,2H),4.33(q,J＝8.4Hz,2H),3.56(s,2H),3.03(t,J＝11.4Hz,2H),2.82(tt,J＝11.4,3.6Hz,1H),2.19(t,J＝12.0Hz,2H),2.01–1.98(m,2H),1.82(qd,J＝12.6,3.6Hz,2H).1 H NMR (600 MHz, CDCl3 ) δ (ppm): 8.07 (s, 1H), 7.51 (dd, J=8.2, 5.4 Hz, 1H), 7.28-7.25 (m, 1H), 7.03-6.98 (m, 3H), 6.92(d, J=1.8Hz, 1H), 6.86–6.82(m, 2H), 4.33(q, J=8.4Hz, 2H), 3.56(s, 2H), 3.03(t, J=11.4 Hz, 2H), 2.82 (tt, J=11.4, 3.6Hz, 1H), 2.19 (t, J=12.0Hz, 2H), 2.01–1.98 (m, 2H), 1.82 (qd, J=12.6, 3.6Hz) , 2H).
实施例6 5-氟-3-(1-(3-(2,2,3,3-四氟丙氧基)苄基)哌啶-4-基)-1H-吲哚的合Example 6 Synthesis of 5-fluoro-3-(1-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)piperidin-4-yl)-1H-indole成to make
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将5-氟-3-(哌啶-4-基)-1H-吲哚(300mg,1.37mmol)，3-(2,2,3,3-四氟丙氧基)苯甲醛(472mg,2.0mmol)和NaBH3CN(250mg,3.97mmol)在MeOH(10mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(282mg,47％)。The title compound in this step was prepared according to the method described in step 4 of Example 1, namely 5-fluoro-3-(piperidin-4-yl)-1H-indole (300 mg, 1.37 mmol), 3-(2,2 ,3,3-tetrafluoropropoxy)benzaldehyde (472 mg, 2.0 mmol) and NaBH3 CN (250 mg, 3.97 mmol) were prepared by reaction in MeOH (10 mL), and the crude product was subjected to silica gel column chromatography (dichloromethane/ Purified with methanol (v/v)=50/1), concentrated and dried to give the title compound as a pale yellow oil (282 mg, 47%).
MS(ESI,pos.ion)m/z:439.2[M+H]+；MS(ESI, pos.ion) m/z: 439.2 [M+H]+ ;
1H NMR(600MHz,CDCl3)δ(ppm):8.07(s,1H),7.51(dd,J＝9.0,5.4Hz,1H),7.28–7.26(m,1H),7.02(d,J＝7.2Hz,1H),7.01–6.98(m,2H),6.93(d,J＝2.0Hz,1H),6.87–6.81(m,2H),6.07(tt,J＝52.8,5.4Hz,1H),4.38(t,J＝11.9Hz,2H),3.62(s,2H),3.08–3.06(m,2H),2.85(tt,J＝11.9,3.5Hz,1H),2.25(t,J＝11.9,2H),2.07–2.04(m,2H),1.87(qd,J＝12.7,3.5Hz,2H).1 H NMR (600 MHz, CDCl3 ) δ (ppm): 8.07 (s, 1H), 7.51 (dd, J=9.0, 5.4 Hz, 1H), 7.28-7.26 (m, 1H), 7.02 (d, J= 7.2Hz, 1H), 7.01–6.98 (m, 2H), 6.93 (d, J=2.0Hz, 1H), 6.87–6.81 (m, 2H), 6.07 (tt, J=52.8, 5.4Hz, 1H), 4.38(t, J＝11.9Hz, 2H), 3.62(s, 2H), 3.08–3.06(m, 2H), 2.85(tt, J＝11.9, 3.5Hz, 1H), 2.25(t, J＝11.9, 2H), 2.07–2.04 (m, 2H), 1.87 (qd, J=12.7, 3.5Hz, 2H).
实施例7 5-氯-3-(1-(3-(2,2,2-三氟乙氧基)苄基)哌啶-4-基)-1H-吲哚的合成Example 7 Synthesis of 5-chloro-3-(1-(3-(2,2,2-trifluoroethoxy)benzyl)piperidin-4-yl)-1H-indole
步骤1)4-(5-氯-1H-吲哚-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成Step 1) Synthesis of 4-(5-chloro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
本步骤标题化合物参照实施例1步骤1所描述的方法制备得到，即将5-氯吲哚(5.0g,33.1mmol)、4-氧代哌啶-1-羧酸叔丁酯(8.0g,40.2mmol)和氢氧化钾(3.70g,66.0mmol)在甲醇(50mL)中反应制备，过滤干燥得到标题化合物为黄色固体(9.12g,83％)。The title compound of this step was prepared according to the method described in step 1 of Example 1, namely 5-chloroindole (5.0 g, 33.1 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (8.0 g, 40.2 mmol) mmol) and potassium hydroxide (3.70 g, 66.0 mmol) in methanol (50 mL), which was filtered and dried to give the title compound as a yellow solid (9.12 g, 83%).
MS(ESI,pos.ion)m/z:333.1[M+H]+；MS(ESI, pos.ion) m/z: 333.1 [M+H]+ ;
1H NMR(400MHz,CDCl3)δ(ppm):8.31(s,1H),7.56(d,J＝2.0Hz,1H),7.22(d,J＝8.4Hz,1H),7.13(dd,J＝8.6,2.0Hz,1H),7.02(d,J＝2.0Hz,1H),6.09(s,1H),4.13(d,J＝2.0Hz,2H),3.67(t,J＝5.6Hz,2H),2.54(brs,2H),1.48(s,9H).1 H NMR (400 MHz, CDCl3 ) δ (ppm): 8.31 (s, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.13 (dd, J ＝8.6, 2.0Hz, 1H), 7.02(d, J＝2.0Hz, 1H), 6.09(s, 1H), 4.13(d, J＝2.0Hz, 2H), 3.67(t, J＝5.6Hz, 2H) ), 2.54(brs, 2H), 1.48(s, 9H).
步骤2)4-(5-氯-1H-吲哚-3-基)哌啶-1-羧酸叔丁酯的合成Step 2) Synthesis of 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid tert-butyl ester
本步骤标题化合物参照实施例1步骤2所描述的方法制备得到，即将4-(5-氯-1H-吲哚-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯(9.0g,27.1mmol)和Pd/C(3.0g,10％)在THF(30mL)和MeOH(20mL)的混合溶剂中反应制备，粗产物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝10/1)纯化，浓缩干燥得到标题化合物为白色固体(7.15g,79％)。The title compound in this step was prepared according to the method described in Example 1, Step 2, namely 4-(5-chloro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid Tert-butyl ester (9.0 g, 27.1 mmol) and Pd/C (3.0 g, 10%) were prepared by reacting in a mixed solvent of THF (30 mL) and MeOH (20 mL). The crude product was subjected to silica gel column chromatography (petroleum ether/acetic acid) Ethyl ester (v/v)=10/1) was purified and concentrated to dryness to give the title compound as a white solid (7.15 g, 79%).
1H NMR(400MHz,CDCl3)δ(ppm):8.30(s,1H),7.57(d,J＝2.0Hz,1H),7.22(d,J＝8.6Hz,1H),7.12(dd,J＝8.6,2.0Hz,1H),7.01(d,J＝2.0Hz,1H),4.09–4.03(m,2H),2.98–2.88(m,2H),2.87(brs,1H),1.95–1.91(m,2H),1.53–1.47(m,2H),1.43(s,9H).1 H NMR (400 MHz, CDCl3 ) δ (ppm): 8.30 (s, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.12 (dd, J =8.6,2.0Hz,1H),7.01(d,J=2.0Hz,1H),4.09-4.03(m,2H),2.98-2.88(m,2H),2.87(brs,1H),1.95-1.91( m,2H),1.53–1.47(m,2H),1.43(s,9H).
步骤3)5-氯-3-(哌啶-4-基)-1H-吲哚的合成Step 3) Synthesis of 5-chloro-3-(piperidin-4-yl)-1H-indole
本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将4-(5-氯-1H-吲哚-3-基)哌啶-1-羧酸叔丁酯(7.0g,20.9mmol)和氯化氢的乙酸乙酯溶液(20mL,2mmol/mL)在二氯甲烷(50mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝30/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(4.55g,93％)。The title compound of this step was prepared according to the method described in step 3 of Example 1, namely tert-butyl 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylate (7.0 g, 20.9 mmol) ) and ethyl acetate solution of hydrogen chloride (20 mL, 2 mmol/mL) in dichloromethane (50 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) , concentrated and dried to give the title compound as a pale yellow oil (4.55 g, 93%).
MS(ESI,pos.ion)m/z:235.1[M+H]+；MS(ESI, pos.ion) m/z: 235.1[M+H]+ ;
1H NMR(400MHz,CDCl3)δ(ppm):8.27(s,1H),7.58(d,J＝2.0Hz,1H),7.22(d,J＝8.4Hz,1H),7.14–7.11(m,1H),7.02(d,J＝2.0Hz,1H),3.05–3.02(m,2H),2.81(tt,J＝12.0,3.0Hz,1H),2.65–2.60(m,2H),1.86–1.81(m,2H),1.54(qd,J＝12.0,3.6Hz,2H).1 H NMR (400 MHz, CDCl3 ) δ (ppm): 8.27 (s, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.14-7.11 (m ,1H),7.02(d,J＝2.0Hz,1H),3.05-3.02(m,2H),2.81(tt,J＝12.0,3.0Hz,1H),2.65-2.60(m,2H),1.86- 1.81(m, 2H), 1.54(qd, J=12.0, 3.6Hz, 2H).
步骤4)5-氯-3-(1-(3-(2,2,2-三氟乙氧基)苄基)哌啶-4-基)-1H-吲哚的合成Step 4) Synthesis of 5-chloro-3-(1-(3-(2,2,2-trifluoroethoxy)benzyl)piperidin-4-yl)-1H-indole
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将5-氯-3-(哌啶-4-基)-1H-吲哚(300mg,1.28mmol)，3-(2,2,2-三氟乙氧基)苯甲醛(450mg,2.20mmol)和NaBH3CN(158mg,2.5mmol)在MeOH(10mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(276mg,51％)。The title compound in this step was prepared according to the method described in step 4 of Example 1, namely 5-chloro-3-(piperidin-4-yl)-1H-indole (300 mg, 1.28 mmol), 3-(2,2 , 2-Trifluoroethoxy)benzaldehyde (450 mg, 2.20 mmol) and NaBH3 CN (158 mg, 2.5 mmol) were prepared by reaction in MeOH (10 mL), and the crude product was subjected to silica gel column chromatography (dichloromethane/methanol ( v/v)=50/1) Purification, concentration and drying to give the title compound as a pale yellow oil (276 mg, 51%).
MS(ESI,pos.ion)m/z:423.1[M+H]+；MS(ESI, pos.ion) m/z: 423.1[M+H]+ ;
1H NMR(600MHz,CDCl3)δ(ppm):8.07(s,1H),7.52(d,J＝8.4Hz,1H),7.32(d,J＝1.2Hz,1H),7.28–7.26(m,1H),7.07–7.04(m,1H),7.01(d,J＝7.8Hz,1H),6.99(s,1H),6.91(d,J＝1.8Hz,1H),6.85(dd,J＝7.8,1.8Hz,1H),4.35(q,J＝8.4Hz,2H),3.57(s,2H),3.02(t,J＝11.4Hz,2H),2.83–2.75(m,1H),2.19(t,J＝12.0Hz,2H),2.03–1.98(m,2H),1.86–1.77(m,2H).1 H NMR (600 MHz, CDCl3 ) δ (ppm): 8.07 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.32 (d, J=1.2 Hz, 1H), 7.28-7.26 (m ,1H),7.07–7.04(m,1H),7.01(d,J=7.8Hz,1H),6.99(s,1H),6.91(d,J=1.8Hz,1H),6.85(dd,J= 7.8,1.8Hz,1H),4.35(q,J=8.4Hz,2H),3.57(s,2H),3.02(t,J=11.4Hz,2H),2.83–2.75(m,1H),2.19( t, J=12.0Hz, 2H), 2.03–1.98 (m, 2H), 1.86–1.77 (m, 2H).
实施例8 5-氯-3-(1-(3-(2,2,3,3-四氟丙氧基)苄基)哌啶-4-基)-1H-吲哚的合Example 8 Synthesis of 5-chloro-3-(1-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)piperidin-4-yl)-1H-indole成to make
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将5-氯-3-(哌啶-4-基)-1H-吲哚(300mg,1.28mmol)，3-(2,2,3,3-四氟丙氧基)苯甲醛(472mg,2.0mmol)和NaBH3CN(158mg,2.5mmol)在MeOH(10mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(331mg,57％)。The title compound in this step was prepared according to the method described in step 4 of Example 1, namely 5-chloro-3-(piperidin-4-yl)-1H-indole (300 mg, 1.28 mmol), 3-(2,2 ,3,3-tetrafluoropropoxy)benzaldehyde (472 mg, 2.0 mmol) and NaBH3 CN (158 mg, 2.5 mmol) were prepared by reaction in MeOH (10 mL), and the crude product was subjected to silica gel column chromatography (dichloromethane/ Purified with methanol (v/v)=50/1), concentrated and dried to give the title compound as a pale yellow oil (331 mg, 57%).
MS(ESI,pos.ion)m/z:455.2[M+H]+；MS(ESI, pos.ion) m/z: 455.2 [M+H]+ ;
1H NMR(600MHz,CDCl3)δ(ppm):8.03(s,1H),7.51(d,J＝8.4Hz,1H),7.31(d,J＝1.8Hz,1H),7.25(d,J＝7.8Hz,1H),7.07–7.04(m,1H),7.01(d,J＝7.8Hz,1H),6.96(s,1H),6.94(d,J＝1.8Hz,1H),6.84–6.82(m,1H),6.07(tt,J＝53.4,5.4Hz,1H),4.34(t,J＝12.0Hz,2H),3.53(s,2H),2.99(t,J＝11.4Hz,2H),2.79(tt,J＝12.0,3.6Hz,1H),2.17–2.14(m,2H),2.01–1.98(m,2H),1.82–1.77(m,2H).1 H NMR (600 MHz, CDCl3 ) δ (ppm): 8.03 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31 (d, J=1.8 Hz, 1H), 7.25 (d, J = 7.8Hz, 1H), 7.07–7.04 (m, 1H), 7.01 (d, J=7.8Hz, 1H), 6.96 (s, 1H), 6.94 (d, J=1.8Hz, 1H), 6.84–6.82 (m,1H),6.07(tt,J=53.4,5.4Hz,1H),4.34(t,J=12.0Hz,2H),3.53(s,2H),2.99(t,J=11.4Hz,2H) , 2.79 (tt, J=12.0, 3.6Hz, 1H), 2.17–2.14 (m, 2H), 2.01–1.98 (m, 2H), 1.82–1.77 (m, 2H).
实施例9 6-氟-3-(1-(3-(2,2,2-三氟乙氧基)苄基)哌啶-4-基)-1H-吲哚的合成Example 9 Synthesis of 6-fluoro-3-(1-(3-(2,2,2-trifluoroethoxy)benzyl)piperidin-4-yl)-1H-indole
步骤1)4-(6-氟-1H-吲哚-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成Step 1) Synthesis of 4-(6-fluoro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester
本步骤标题化合物参照实施例1步骤1所描述的方法制备得到，即将6-氟吲哚(3.0g,22.2mmol)、4-氧代哌啶-1-羧酸叔丁酯(5.3g,26.6mmol)和氢氧化钾(1.78g,31.8mmol)在甲醇(50mL)中反应制备，过滤干燥得到标题化合物为黄色固体(6.87g,98％)。The title compound in this step was prepared according to the method described in step 1 of Example 1, namely, 6-fluoroindole (3.0 g, 22.2 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (5.3 g, 26.6 g) mmol) and potassium hydroxide (1.78 g, 31.8 mmol) in methanol (50 mL), which was filtered and dried to give the title compound as a yellow solid (6.87 g, 98%).
MS(ESI,pos.ion)m/z:317.3[M+H]+；MS(ESI, pos.ion) m/z: 317.3 [M+H]+ ;
1H NMR(600MHz,DMSO-d6)δ(ppm):11.23(s,1H),7.80(dd,J＝9.0,5.4Hz,1H),7.42(s,1H),7.15(dd,J＝10.2,2.4Hz,1H),6.89(td,J＝11.4,2.4Hz,1H),6.12(s,1H),4.03(brs,2H),3.55(d,J＝5.4Hz,2H),2.48(brs,2H),1.43(s,9H).1 H NMR (600 MHz, DMSO-d6 ) δ (ppm): 11.23 (s, 1H), 7.80 (dd, J=9.0, 5.4 Hz, 1H), 7.42 (s, 1H), 7.15 (dd, J= 10.2, 2.4Hz, 1H), 6.89(td, J＝11.4, 2.4Hz, 1H), 6.12(s, 1H), 4.03(brs, 2H), 3.55(d, J＝5.4Hz, 2H), 2.48( brs,2H),1.43(s,9H).
步骤2)4-(6-氟-1H-吲哚-3-基)哌啶-1-羧酸叔丁酯的合成Step 2) Synthesis of 4-(6-fluoro-1H-indol-3-yl)piperidine-1-carboxylate tert-butyl ester
本步骤标题化合物参照实施例1步骤2所描述的方法制备得到，即将4-(6-氟-1H-吲哚-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯(3.5g,11.0mmol)和Pd/C(310mg,10％)在THF(15mL)和MeOH(10mL)的混合溶剂中反应制备，粗产物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝10/1)纯化，浓缩干燥得到标题化合物为白色固体(3.16g,90.0％)。The title compound in this step was prepared according to the method described in Example 1, Step 2, namely 4-(6-fluoro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid Tert-butyl ester (3.5 g, 11.0 mmol) and Pd/C (310 mg, 10%) were prepared by reacting in a mixed solvent of THF (15 mL) and MeOH (10 mL), and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate) The ester (v/v)=10/1) was purified and concentrated to dryness to give the title compound as a white solid (3.16 g, 90.0%).
MS(ESI,pos.ion)m/z:219.3[M+H-100]+；MS(ESI, pos.ion) m/z: 219.3 [M+H-100]+ ;
1H NMR(600MHz,DMSO-d6)δ(ppm):10.87(s,1H),7.53(dd,J＝9.0,5.4Hz,1H),7.09(dd,J＝9.6,2.4Hz,2H),6.81(td,J＝9.6,2.4Hz,1H),4.04(t,J＝7.2Hz,2H),2.97–2.77(m,3H),1.94–1.91(m,2H),1.50–1.47(m,2H),1.41(s,9H).1 H NMR (600 MHz, DMSO-d6 ) δ (ppm): 10.87 (s, 1H), 7.53 (dd, J=9.0, 5.4 Hz, 1H), 7.09 (dd, J=9.6, 2.4 Hz, 2H) ,6.81(td,J=9.6,2.4Hz,1H),4.04(t,J=7.2Hz,2H),2.97-2.77(m,3H),1.94-1.91(m,2H),1.50-1.47(m ,2H),1.41(s,9H).
步骤3)6-氟-3-(哌啶-4-基)-1H-吲哚的合成Step 3) Synthesis of 6-fluoro-3-(piperidin-4-yl)-1H-indole
本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将4-(6-氟-1H-吲哚-3-基)哌啶-1-羧酸叔丁酯(3.1g,9.7mmol)和氯化氢的乙酸乙酯溶液(10mL,2mmol/mL)在二氯甲烷(30mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝30/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(1.75g,83％)。The title compound in this step was prepared according to the method described in step 3 of Example 1, namely tert-butyl 4-(6-fluoro-1H-indol-3-yl)piperidine-1-carboxylate (3.1 g, 9.7 mmol) ) and ethyl acetate solution of hydrogen chloride (10 mL, 2 mmol/mL) in dichloromethane (30 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) , concentrated and dried to give the title compound as a pale yellow oil (1.75 g, 83%).
MS(ESI,pos.ion)m/z:219.1[M+H]+；MS(ESI, pos.ion) m/z: 219.1[M+H]+ ;
1H NMR(600MHz,DMSO-d6)δ(ppm):10.83(s,1H),7.53(dd,J＝9.0,5.4Hz,1H),7.09(dd,J＝10.2,2.4Hz,1H),7.05(d,J＝1.8Hz,1H),6.80(ddd,J＝9.6,8.4,2.4Hz,1H),3.00(t,J＝12.0Hz,2H),2.80(tt,J＝11.4,3.0Hz,1H),2.63(td,J＝12.0,1.8Hz,2H),1.86–1.82(m,2H),1.53(qd,J＝12.0,3.6Hz,2H).1 H NMR (600 MHz, DMSO-d6 ) δ (ppm): 10.83 (s, 1H), 7.53 (dd, J=9.0, 5.4 Hz, 1H), 7.09 (dd, J=10.2, 2.4 Hz, 1H) ,7.05(d,J＝1.8Hz,1H),6.80(ddd,J＝9.6,8.4,2.4Hz,1H),3.00(t,J＝12.0Hz,2H),2.80(tt,J＝11.4,3.0 Hz, 1H), 2.63 (td, J=12.0, 1.8Hz, 2H), 1.86–1.82 (m, 2H), 1.53 (qd, J=12.0, 3.6Hz, 2H).
步骤4)6-氟-3-(1-(3-(2,2,2-三氟乙氧基)苄基)哌啶-4-基)-1H-吲哚的合成Step 4) Synthesis of 6-fluoro-3-(1-(3-(2,2,2-trifluoroethoxy)benzyl)piperidin-4-yl)-1H-indole
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将6-氟-3-(哌啶-4-基)-1H-吲哚(300mg,1.37mmol)，3-(2,2,2-三氟乙氧基)苯甲醛(420mg,2.06mmol)和NaBH3CN(173mg,2.06mmol)在MeOH(10mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(260mg,46.6％)。The title compound in this step was prepared according to the method described in step 4 of Example 1, namely 6-fluoro-3-(piperidin-4-yl)-1H-indole (300 mg, 1.37 mmol), 3-(2,2 ,2-trifluoroethoxy)benzaldehyde (420 mg, 2.06 mmol) and NaBH3 CN (173 mg, 2.06 mmol) were prepared by reaction in MeOH (10 mL), and the crude product was subjected to silica gel column chromatography (dichloromethane/methanol ( v/v)=50/1) Purification, concentration and drying to give the title compound as a pale yellow oil (260 mg, 46.6%).
MS(ESI,pos.ion)m/z:407.2[M+H]+；MS(ESI, pos.ion) m/z: 407.2[M+H]+ ;
1H NMR(600MHz,CDCl3)δ(ppm):8.05(s,1H),7.50(dd,J＝8.4,5.4Hz,1H),7.26(t,J＝7.8Hz,1H),7.03–6.98(m,3H),6.92(d,J＝1.8Hz,1H),6.86–6.82(m,2H),4.34(q,J＝8.4Hz,2H),3.57(s,2H),3.02(t,J＝11.4Hz,2H),2.80(tt,J＝11.4,3.6Hz,1H),2.19(t,J＝12.0Hz,2H),2.01–1.98(m,2H),1.82(qd,J＝12.6,3.6Hz,2H).1 H NMR (600 MHz, CDCl3 ) δ (ppm): 8.05 (s, 1H), 7.50 (dd, J=8.4, 5.4 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.03-6.98 (m, 3H), 6.92(d, J=1.8Hz, 1H), 6.86–6.82(m, 2H), 4.34(q, J=8.4Hz, 2H), 3.57(s, 2H), 3.02(t, J=11.4Hz, 2H), 2.80 (tt, J=11.4, 3.6Hz, 1H), 2.19 (t, J=12.0Hz, 2H), 2.01–1.98 (m, 2H), 1.82 (qd, J=12.6 ,3.6Hz,2H).
实施例10 6-氟-3-(1-(3-(2,2,3,3-四氟丙氧基)苄基)哌啶-4-基)-1H-吲哚的合Example 10 Synthesis of 6-fluoro-3-(1-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)piperidin-4-yl)-1H-indole成to make
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将6-氟-3-(哌啶-4-基)-1H-吲哚(300mg,1.37mmol)，3-(2,2,3,3-四氟丙氧基)苯甲醛(487mg,2.06mmol)和NaBH3CN(130mg,2.06mmol)在MeOH(10mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(386mg,64.1％)。The title compound in this step was prepared according to the method described in step 4 of Example 1, namely 6-fluoro-3-(piperidin-4-yl)-1H-indole (300 mg, 1.37 mmol), 3-(2,2 ,3,3-tetrafluoropropoxy)benzaldehyde (487mg, 2.06mmol) andNaBH3CN (130mg, 2.06mmol) were prepared by reaction in MeOH (10mL), and the crude product was subjected to silica gel column chromatography (dichloromethane/ Purified with methanol (v/v)=50/1), concentrated and dried to give the title compound as a pale yellow oil (386 mg, 64.1%).
MS(ESI,pos.ion)m/z:439.2[M+H]+；MS(ESI, pos.ion) m/z: 439.2 [M+H]+ ;
1H NMR(600MHz,CDCl3)δ(ppm):8.07(s,1H),7.51(dd,J＝9.0,5.4Hz,1H),7.27(t,J＝7.8Hz,1H),7.02(d,J＝7.2Hz,1H),7.00(dd,J＝9.6,2.4Hz,1H),6.98(s,1H),6.92(d,J＝1.8Hz,1H),6.87–6.81(m,2H),6.06(tt,J＝52.8,5.4Hz,1H),4.33(t,J＝12.0Hz,2H),3.56(s,2H),3.03(t,J＝12.0Hz,2H),2.80(tt,J＝12.0,3.0Hz,1H),2.24–2.14(m,2H),2.03–2.00(m,2H),1.83(qd,J＝12.6,3.6Hz,2H).1 H NMR (600 MHz, CDCl3 ) δ (ppm): 8.07 (s, 1H), 7.51 (dd, J=9.0, 5.4 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.02 (d ,J=7.2Hz,1H),7.00(dd,J=9.6,2.4Hz,1H),6.98(s,1H),6.92(d,J=1.8Hz,1H),6.87–6.81(m,2H) ,6.06(tt,J＝52.8,5.4Hz,1H),4.33(t,J＝12.0Hz,2H),3.56(s,2H),3.03(t,J＝12.0Hz,2H),2.80(tt, J=12.0, 3.0Hz, 1H), 2.24–2.14 (m, 2H), 2.03–2.00 (m, 2H), 1.83 (qd, J=12.6, 3.6Hz, 2H).
实施例11 6-氯-3-(1-(3-(2,2,2-三氟乙氧基)苄基)哌啶-4-基)-1H-吲哚的合成Example 11 Synthesis of 6-chloro-3-(1-(3-(2,2,2-trifluoroethoxy)benzyl)piperidin-4-yl)-1H-indole
步骤1)4-(6-氯-1H-吲哚-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成Step 1) Synthesis of 4-(6-chloro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
本步骤标题化合物参照实施例1步骤1所描述的方法制备得到，即将6-氯吲哚(3.0g,19.8mmol)、4-氧代哌啶-1-羧酸叔丁酯(4.7g,24.0mmol)和氢氧化钾(1.58g,28.2mmol)在甲醇(50mL)中反应制备，过滤干燥得到标题化合物为黄色固体(6.1g,92.8％)。The title compound in this step was prepared according to the method described in step 1 of Example 1, namely 6-chloroindole (3.0 g, 19.8 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (4.7 g, 24.0 mmol) mmol) and potassium hydroxide (1.58 g, 28.2 mmol) in methanol (50 mL), which was filtered and dried to give the title compound as a yellow solid (6.1 g, 92.8%).
MS(ESI,pos.ion)m/z:333.2[M+H]+；MS(ESI, pos.ion) m/z: 333.2[M+H]+ ;
1H NMR(600MHz,DMSO-d6)δ(ppm):11.31(s,1H),7.83(d,J＝8.4Hz,1H),7.48(s,1H),7.44(d,J＝1.8Hz,1H),7.06(dd,J＝8.4,1.8Hz,1H),6.13(s,1H),4.05(brs,2H),3.57(t,J＝4.8Hz,2H),3.37(brs,2H),1.45(s,9H).1 H NMR (600 MHz, DMSO-d6 ) δ (ppm): 11.31 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.48 (s, 1H), 7.44 (d, J=1.8 Hz ,1H),7.06(dd,J=8.4,1.8Hz,1H),6.13(s,1H),4.05(brs,2H),3.57(t,J=4.8Hz,2H),3.37(brs,2H) ,1.45(s,9H).
步骤2)4-(6-氯-1H-吲哚-3-基)哌啶-1-羧酸叔丁酯的合成Step 2) Synthesis of 4-(6-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid tert-butyl ester
本步骤标题化合物参照实施例1步骤2所描述的方法制备得到，即将4-(6-氯-1H-吲哚-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯(3.5g,10.5mmol)和Pd/C(310mg,10％)在THF(15mL)和MeOH(10mL)的混合溶剂中反应制备，粗产物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝10/1)纯化，浓缩干燥得到标题化合物为白色固体(2.52g,72.0％)。The title compound in this step was prepared according to the method described in Example 1, Step 2, namely 4-(6-chloro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid Tert-butyl ester (3.5 g, 10.5 mmol) and Pd/C (310 mg, 10%) were prepared by reacting in a mixed solvent of THF (15 mL) and MeOH (10 mL). The crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate) The ester (v/v)=10/1) was purified and concentrated to dryness to give the title compound as a white solid (2.52 g, 72.0%).
MS(ESI,pos.ion)m/z:235.1[M+H-100]+；MS(ESI, pos.ion) m/z: 235.1 [M+H-100]+ ;
1H NMR(600MHz,DMSO-d6)δ(ppm):10.95(s,1H),7.55(d,J＝8.4Hz,1H),7.37(d,J＝1.8Hz,1H),7.15(d,J＝1.8Hz,1H),6.97(dd,J＝8.4,1.8Hz,1H),4.09–4.01(m,2H),2.97–2.88(m,2H),2.87(brs,1H),1.94–1.90(m,2H),1.53–1.45(m,2H),1.41(s,9H).1 H NMR (600MHz, DMSO-d6 ) δ(ppm): 10.95(s, 1H), 7.55(d, J=8.4Hz, 1H), 7.37(d, J=1.8Hz, 1H), 7.15(d) , J=1.8Hz, 1H), 6.97 (dd, J=8.4, 1.8Hz, 1H), 4.09–4.01 (m, 2H), 2.97–2.88 (m, 2H), 2.87 (brs, 1H), 1.94– 1.90(m, 2H), 1.53–1.45(m, 2H), 1.41(s, 9H).
步骤3)6-氯-3-(哌啶-4-基)-1H-吲哚的合成Step 3) Synthesis of 6-chloro-3-(piperidin-4-yl)-1H-indole
本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将4-(6-氯-1H-吲哚-3-基)哌啶-1-羧酸叔丁酯(2.5g,7.5mmol)和氯化氢的乙酸乙酯溶液(10mL,2mmol/mL)在二氯甲烷(30mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝30/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(1.58g,90.0％)。The title compound in this step was prepared according to the method described in step 3 of Example 1, namely tert-butyl 4-(6-chloro-1H-indol-3-yl)piperidine-1-carboxylate (2.5 g, 7.5 mmol) ) and ethyl acetate solution of hydrogen chloride (10 mL, 2 mmol/mL) in dichloromethane (30 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) , concentrated and dried to give the title compound as a pale yellow oil (1.58 g, 90.0%).
MS(ESI,pos.ion)m/z:235.1[M+H]+；MS(ESI, pos.ion) m/z: 235.1[M+H]+ ;
1H NMR(600MHz,DMSO-d6)δ(ppm):10.92(s,1H),7.55(d,J＝8.4Hz,1H),7.37(d,J＝1.8Hz,1H),7.10(s,1H),6.95(dd,J＝8.4,1.8Hz,1H),3.02–2.99(m,2H),2.80(tt,J＝12.0,3.0Hz,1H),2.65–2.59(m,2H),1.86–1.80(m,2H),1.53(qd,J＝12.0,3.6Hz,2H).1 H NMR (600 MHz, DMSO-d6 ) δ (ppm): 10.92 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.37 (d, J=1.8 Hz, 1H), 7.10 (s ,1H),6.95(dd,J=8.4,1.8Hz,1H),3.02–2.99(m,2H),2.80(tt,J=12.0,3.0Hz,1H),2.65–2.59(m,2H), 1.86–1.80(m, 2H), 1.53(qd, J=12.0, 3.6Hz, 2H).
步骤4)6-氯-3-(1-(3-(2,2,2-三氟乙氧基)苄基)哌啶-4-基)-1H-吲哚的合成Step 4) Synthesis of 6-chloro-3-(1-(3-(2,2,2-trifluoroethoxy)benzyl)piperidin-4-yl)-1H-indole
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将6-氯-3-(哌啶-4-基)-1H-吲哚(300mg,1.28mmol)，3-(2,2,2-三氟乙氧基)苯甲醛(530mg,2.6mmol)和NaBH3CN(164mg,2.6mmol)在MeOH(10mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(208mg,38.5％)。The title compound in this step was prepared according to the method described in step 4 of Example 1, namely 6-chloro-3-(piperidin-4-yl)-1H-indole (300 mg, 1.28 mmol), 3-(2,2 , 2-Trifluoroethoxy)benzaldehyde (530 mg, 2.6 mmol) and NaBH3 CN (164 mg, 2.6 mmol) were prepared by reaction in MeOH (10 mL), and the crude product was subjected to silica gel column chromatography (dichloromethane/methanol ( v/v)=50/1) Purification, concentration and drying to give the title compound as a pale yellow oil (208 mg, 38.5%).
MS(ESI,pos.ion)m/z:423.1[M+H]+；MS(ESI, pos.ion) m/z: 423.1[M+H]+ ;
1H NMR(600MHz,CDCl3)δ(ppm):8.07(s,1H),7.51(d,J＝8.4Hz,1H),7.31(d,J＝1.2Hz,1H),7.26(t,J＝7.8Hz,1H),7.04(dd,J＝8.4,1.2Hz,1H),7.02(d,J＝7.8Hz,1H),6.99(s,1H),6.93(d,J＝1.8Hz,1H),6.84(dd,J＝7.8,1.8Hz,1H),4.34(q,J＝8.4Hz,2H),3.56(s,2H),3.01(t,J＝11.4Hz,2H),2.83–2.74(m,1H),2.19(t,J＝12.0Hz,2H),2.02–1.98(m,2H),1.85–1.77(m,2H).1 H NMR (600 MHz, CDCl3 ) δ (ppm): 8.07 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31 (d, J=1.2 Hz, 1H), 7.26 (t, J =7.8Hz,1H),7.04(dd,J=8.4,1.2Hz,1H),7.02(d,J=7.8Hz,1H),6.99(s,1H),6.93(d,J=1.8Hz,1H) ), 6.84(dd, J＝7.8, 1.8Hz, 1H), 4.34(q, J＝8.4Hz, 2H), 3.56(s, 2H), 3.01(t, J＝11.4Hz, 2H), 2.83–2.74 (m, 1H), 2.19 (t, J=12.0Hz, 2H), 2.02–1.98 (m, 2H), 1.85–1.77 (m, 2H).
实施例12 6-氯-3-(1-(3-(2,2,3,3-四氟丙氧基)苄基)哌啶-4-基)-1H-吲哚的合Example 12 Synthesis of 6-chloro-3-(1-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)piperidin-4-yl)-1H-indole成to make
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将6-氯-3-(哌啶-4-基)-1H-吲哚(300mg,1.28mmol)，3-(2,2,3,3-四氟丙氧基)苯甲醛(453mg,1.92mmol)和NaBH3CN(120mg,1.92mmol)在MeOH(10mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(265mg,45.6％)。The title compound in this step was prepared according to the method described in step 4 of Example 1, namely 6-chloro-3-(piperidin-4-yl)-1H-indole (300 mg, 1.28 mmol), 3-(2,2 ,3,3-tetrafluoropropoxy)benzaldehyde (453 mg, 1.92 mmol) and NaBH3 CN (120 mg, 1.92 mmol) were prepared by reaction in MeOH (10 mL), and the crude product was subjected to silica gel column chromatography (dichloromethane/ Purified with methanol (v/v)=50/1), concentrated and dried to give the title compound as a pale yellow oil (265 mg, 45.6%).
MS(ESI,pos.ion)m/z:455.1[M+H]+；MS(ESI, pos.ion) m/z: 455.1 [M+H]+ ;
1H NMR(600MHz,CDCl3)δ(ppm):8.00(s,1H),7.51(d,J＝8.4Hz,1H),7.31(d,J＝1.8Hz,1H),7.26(d,J＝7.8Hz,1H),7.05(dd,J＝8.4,1.8Hz,1H),7.02(d,J＝7.8Hz,1H),6.96(s,1H),6.94(d,J＝1.8Hz,1H),6.81(dd,J＝8.4,2.4Hz,1H),6.06(tt,J＝53.4,5.4Hz,1H),4.34(t,J＝12.0Hz,2H),3.53(s,2H),3.02–2.98(m,2H),2.79(tt,J＝12.0,3.6Hz,1H),2.15(td,J＝12.0,2.4Hz,2H),2.02–1.98(m,2H),1.79(qd,J＝12.6,3.6Hz,2H).1 H NMR (600 MHz, CDCl3 ) δ (ppm): 8.00 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31 (d, J=1.8 Hz, 1H), 7.26 (d, J ＝7.8Hz,1H),7.05(dd,J＝8.4,1.8Hz,1H),7.02(d,J＝7.8Hz,1H),6.96(s,1H),6.94(d,J＝1.8Hz,1H) ),6.81(dd,J＝8.4,2.4Hz,1H),6.06(tt,J＝53.4,5.4Hz,1H),4.34(t,J＝12.0Hz,2H),3.53(s,2H),3.02 –2.98(m,2H),2.79(tt,J=12.0,3.6Hz,1H),2.15(td,J=12.0,2.4Hz,2H),2.02–1.98(m,2H),1.79(qd,J =12.6,3.6Hz,2H).
实施例13 6-氯-3-(1-(3-(2,2,3,3-四氟丙氧基)苄基)-1,2,3,6-四氢吡啶-4-Example 13 6-Chloro-3-(1-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)-1,2,3,6-tetrahydropyridine-4-基)-1H-吲哚的合成Synthesis of )-1H-indole
步骤1)6-氯-3-(1,2,3,6-四氢吡啶-4-基)-1H-吲哚的合成Step 1) Synthesis of 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole
本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将4-(6-氯-1H-吲哚-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯(1.0g,3.0mmol)和氯化氢的乙酸乙酯溶液(10mL,2mmol/mL)在二氯甲烷(20mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝30/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(370mg,53％)。The title compound in this step was prepared according to the method described in step 3 of Example 1, namely 4-(6-chloro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid The tert-butyl ester (1.0 g, 3.0 mmol) was prepared by reacting hydrogen chloride in ethyl acetate (10 mL, 2 mmol/mL) in dichloromethane (20 mL). The crude product was subjected to silica gel column chromatography (dichloromethane/methanol (v /v)=30/1) Purification, concentration and drying to give the title compound as a pale yellow oil (370 mg, 53%).
MS(ESI,pos.ion)m/z:233.1[M+H]+；MS(ESI, pos.ion) m/z: 233.1[M+H]+ ;
1H NMR(600MHz,DMSO-d6)δ(ppm):11.35(s,1H),7.80(d,J＝8.4Hz,1H),7.45(s,1H),7.43(d,J＝1.8Hz,1H),7.04(dd,J＝8.4,1.8Hz,1H),6.14(brs,1H),3.52(d,J＝2.4Hz,2H),3.06(t,J＝6.0Hz,2H),1.81(brs,2H).1 H NMR (600 MHz, DMSO-d6 ) δ (ppm): 11.35 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.43 (d, J=1.8 Hz) ,1H),7.04(dd,J＝8.4,1.8Hz,1H),6.14(brs,1H),3.52(d,J＝2.4Hz,2H),3.06(t,J＝6.0Hz,2H),1.81 (brs,2H).
步骤2)6-氯-3-(1-(3-(2,2,3,3-四氟丙氧基)苄基)-1,2,3,6-四氢吡啶-4-基)-Step 2) 6-Chloro-3-(1-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)-1,2,3,6-tetrahydropyridin-4-yl) -1H-吲哚的合成Synthesis of 1H-Indole
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将6-氯-3-(1,2,3,6-四氢吡啶-4-基)-1H-吲哚(130mg,0.56mmol)，3-(2,2,3,3-四氟丙氧基)苯甲醛(264mg,1.12mmol)和NaBH3CN(70mg,1.12mmol)在MeOH(10mL)中反应制备，粗产物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化，浓缩干燥得到标题化合物为淡黄色油状物(170mg,67.2％)。The title compound in this step was prepared according to the method described in Example 1, Step 4, namely 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (130 mg, 0.56 mmol), 3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde (264 mg, 1.12 mmol) andNaBH3CN (70 mg, 1.12 mmol) in MeOH (10 mL) were prepared by reacting the crude product with Purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1), concentrated and dried to give the title compound as a pale yellow oil (170 mg, 67.2%).
MS(ESI,pos.ion)m/z:453.1[M+H]+；MS(ESI, pos.ion) m/z: 453.1[M+H]+ ;
1H NMR(600MHz,DMSO-d6)δ(ppm):11.38(s,1H),7.82(d,J＝9.0Hz,1H),7.53(s,1H),7.45(s,1H),7.43(t,J＝7.8Hz,1H),7.21(s,1H),7.17(d,J＝7.2Hz,1H),7.13(d,J＝7.8Hz,1H),7.06(d,J＝8.4Hz,1H),6.68(tt,J＝52.0,4.8Hz,1H),6.14(brs,1H),4.61(t,J＝13.2Hz,2H),4.19(brs,2H),3.64(brs,2H),2.73(brs,2H),2.08(brs,2H).1 H NMR (600 MHz, DMSO-d6 ) δ (ppm): 11.38 (s, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.53 (s, 1H), 7.45 (s, 1H), 7.43 (t, J=7.8Hz, 1H), 7.21 (s, 1H), 7.17 (d, J=7.2Hz, 1H), 7.13 (d, J=7.8Hz, 1H), 7.06 (d, J=8.4Hz) ,1H),6.68(tt,J＝52.0,4.8Hz,1H),6.14(brs,1H),4.61(t,J＝13.2Hz,2H),4.19(brs,2H),3.64(brs,2H) ,2.73(brs,2H),2.08(brs,2H).
生物试验biological test
实施例A.用放射配基结合分析法评价本发明化合物对表达在CHO细胞上的人源5-HT6受体的亲和力Example A. Evaluation of Affinity of Compounds of the Invention for Human 5-HT6 Receptor Expressed on CHO Cells Using Radioligand Binding Assay
将32μg制备好的表达有人源5-HT6受体的CHO细胞膜蛋白、2nM放射性标记物[3H]LSD、不同测试浓度的化合物、100μM 5-HT(5-HT用于去除非特异性结合位点)以及测试缓冲液混合均匀，然后将混合液于37℃下孵育120min；其中，测试缓冲液成分为：50mM Tris-HCl(pH 7.4)，10mM MgCl2，0.5mM EDTA，10μM帕吉林和20mg/L蛋白酶抑制剂。32 μg prepared CHO cell membrane protein expressing human 5-HT6 receptor, 2 nM radiolabel [3H]LSD, compounds at different test concentrations, 100 μM 5-HT (5-HT was used to remove non-specific binding sites) ) and the test buffer were mixed evenly, and then the mixture was incubated at 37°C for 120min; wherein, the test buffer was composed of: 50mM Tris-HCl (pH 7.4), 10mM MgCl2 , 0.5mM EDTA, 10μM Pagiline and 20mg/ L protease inhibitor.
孵育后，将上述混合液在真空条件下用玻璃纤维过滤器(GF/B,Packard)过滤，滤器的滤膜在过滤前先用0.3％PEI预浸。过滤后，用50mM Tris-HCl将过滤膜冲洗几次。待滤膜干燥后，用闪烁混合液在闪烁计数器(Topcount,Packard)上计数滤膜的放射活性。标准参考化合物为5-HT，且在每次实验中均测试多个浓度以获取其竞争抑制曲线，经Hill方程曲线进行非线性回归分析，得IC50值，再经ChengPrusoff方程式计算，得Ki值。After incubation, the above mixture was filtered through a glass fiber filter (GF/B, Packard) under vacuum conditions, and the filter membrane of the filter was pre-soaked with 0.3% PEI before filtration. After filtration, the filter membrane was rinsed several times with 50 mMTris -HCl. After the filters were dried, the radioactivity of the filters was counted in a scintillation counter (Topcount, Packard) using a scintillation cocktail. The standard reference compound is 5-HT, and multiple concentrations were tested in each experiment to obtain its competitive inhibition curve. The Hill equation curve was used for nonlinear regression analysis to obtain the IC50 value, and then the ChengPrusoff equation was used to calculate the Ki value. .
按照上述方法进行本发明化合物对表达在CHO细胞上的人源5-HT6受体的亲和力测试，结果表明本发明化合物对人源5-HT6受体具有较好的亲和力。在具体的实施例中，本发明化合物对表达在CHO细胞上的人源5-HT6受体结合的Ki值小于0.1μM；优选的，Ki值小于0.05μM。更具体地，实施例9、实施例11和实施例12制备得到的化合物的Ki值小于0.1μM；实施例10制备得到的化合物的Ki值小于0.05μM。The affinity test of the compound of the present invention to the human 5-HT6 receptor expressed on CHO cells was carried out according to the above method, and the results showed that the compound of the present invention had a good affinity to the human 5-HT6 receptor. In a specific embodiment, the Ki value of the compound of the present invention for binding to human 5-HT6 receptor expressed on CHO cells is less than 0.1 μM; preferably, the Ki value is less than 0.05 μM. More specifically, the Ki value of the compounds prepared in Example 9, Example 11 and Example 12 is less than 0.1 μM; the Ki value of the compound prepared in Example 10 is less than 0.05 μM.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“一实施方案”、“示例”、“具体示例”或“一些示例”等的描述意指结合该实施例、实施方案或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例、实施方案或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例、实施方案或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例、实施方案或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例、实施方案或示例以及不同实施例、实施方案或示例的特征进行结合和组合。In the description of this specification, reference to the terms "one embodiment," "some embodiments," "an embodiment," "example," "specific example," or "some examples", etc. A particular feature, structure, material or characteristic described by an embodiment or example is included in at least one embodiment, implementation or example of the invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment, implementation or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations or examples. Furthermore, those skilled in the art may combine and combine the different embodiments, implementations or examples described in this specification and the features of the different embodiments, implementations or examples without conflicting each other.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it should be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. Embodiments are subject to variations, modifications, substitutions and variations.
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