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CN1777582A - Substituted indoline and indole derivatives - Google Patents

Substituted indoline and indole derivatives Download PDF

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CN1777582A
CN1777582A CNA2004800110190A CN200480011019A CN1777582A CN 1777582 A CN1777582 A CN 1777582A CN A2004800110190 A CNA2004800110190 A CN A2004800110190A CN 200480011019 A CN200480011019 A CN 200480011019A CN 1777582 A CN1777582 A CN 1777582A
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alk
cycloalk
indol
dihydro
aryl
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N·汉津
M·罗特莱恩德
W·P·沃特森
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Abstract

本发明涉及通式I的苯胺衍生物或其药学上可接受的盐，以及它们的用途。

Figure 200480011019

This invention relates to aniline derivatives of general formula I or pharmaceutically acceptable salts thereof, and their uses.

Figure 200480011019

Description

取代的二氢吲哚和吲哚衍生物Substituted indoline and indole derivatives

本发明涉及作为KCNQ家族钾离子通道开放剂的新型取代的吲哚和二氢吲哚衍生物。这些化合物用于与KCNQ家族钾离子通道开放有关的障碍和疾病的预防、治疗和抑制，癫痫为一种这类疾病。The present invention relates to novel substituted indole and indoline derivatives as KCNQ family potassium ion channel openers. These compounds are useful for the prevention, treatment and inhibition of disorders and diseases associated with the opening of potassium ion channels of the KCNQ family, epilepsy being one such disease.

                      发明背景Background of the Invention

离子通道为调节离子流动，包括钾、钙、氯和钠流进和流出细胞的细胞蛋白。这种通道存在于所有的动物和人类细胞中，并且影响各种过程，包括神经传导、肌肉收缩和细胞分泌。Ion channels are cellular proteins that regulate the flow of ions, including potassium, calcium, chloride, and sodium, into and out of cells. This channel is present in all animal and human cells and affects a variety of processes, including nerve transmission, muscle contraction and cell secretion.

人类有70多种结构和功能各异的编码钾通道亚型(Jentsch NatureReviews Neuroscience 2000，1，21-30)的基因。在脑部发现的神经元钾通道的主要作用为保持负的静息膜电位以及通过动作电位控制膜复极化。Humans have more than 70 genes encoding potassium channel subtypes (Jentsch Nature Reviews Neuroscience 2000, 1, 21-30) that vary in structure and function. The main role of neuronal potassium channels found in the brain is to maintain a negative resting membrane potential and to control membrane repolarization through action potentials.

钾通道基因的一个亚型为KCNQ家族。已发现五分之四的KCNQ基因突变引起疾病，包括心率不齐、耳聋和癫痫症(Jentsch NatureReviews Neuroscience 2000，1，21-30)。One subtype of potassium channel genes is the KCNQ family. Four out of five mutations in the KCNQ gene have been found to cause disease, including heart arrhythmias, deafness and epilepsy (Jentsch Nature Reviews Neuroscience 2000, 1, 21-30).

认为KCNQ4基因编码与耳蜗的外毛细胞和前庭的I型毛细胞中的钾通道相关的分子，其突变导致遗传性耳聋。Mutations in the KCNQ4 gene, which encodes a molecule associated with potassium channels in the outer hair cells of the cochlea and type I hair cells of the vestibule, are thought to cause hereditary deafness.

KCNQ1(KvLQT1)与心脏中的KCNE1(最小K(+)-通道蛋白)基因的产物共同形成心脏延迟整流K(+)电流。该通道中的突变可引起一种遗传性I型长QT综合症(LQT1)，并与一种耳聋有关(RobbinsPharmacol Ther 2001，90，1-19)。KCNQ1 (KvLQT1) together with the product of the KCNE1 (minimal K(+)-channel protein) gene in the heart form cardiac delayed rectifier K(+) currents. Mutations in this channel cause an inherited type I long QT syndrome (LQT1) and are associated with a form of deafness (Robbins Pharmacol Ther 2001, 90, 1-19).

基因KCNQ2和KCNQ3发现于1988年，并认为在一种被称作良性家族性新生儿抽搐的遗传性癫痫中发生变异(Rogawski Trends inNeurosciences 2000，23，393-398)。由KCNQ2和KCNQ3基因编码的蛋白集中在人大脑区域的皮层和海马的锥体神经元中，该区域与癫痫发作和传播相关(Cooper等人，Proceedings National Academy ofScience USA 2000，97，4914-4919)。The genes KCNQ2 and KCNQ3 were discovered in 1988 and thought to be mutated in a genetic form of epilepsy known as benign familial neonatal convulsions (Rogawski Trends in Neurosciences 2000, 23, 393-398). The proteins encoded by the KCNQ2 and KCNQ3 genes are concentrated in the cortex and pyramidal neurons of the hippocampus in regions of the human brain that are associated with seizures and propagation (Cooper et al., Proceedings National Academy of Science USA 2000, 97, 4914-4919) .

当在活体外表达时，KCNQ2和KCNQ3为两种形成“M-电流”的钾通道亚型。M-电流为存在于多种神经元细胞类型的非活性钾电流。在各种细胞类型中，通过作为在动作电位引发范围内的唯一的持续电流主要控制膜的应激性(Marrion Annual Review Physiology1997，59，483-504)。M-电流的调节对于神经元的应激性具有很大的影响，例如电流的活化将降低神经元的应激性。这些KCNQ通道的开放剂或M-电流的活性剂将降低过度的神经元活性，因此可用于治疗、预防或抑制以过度的神经元活性为特征的癫痫发作和其他疾病和障碍，如神经元超兴奋性包括惊厥、癫痫和神经病变性疼痛。KCNQ2 and KCNQ3 are two subtypes of potassium channels that form "M-currents" when expressed in vitro. The M-current is an inactive potassium current present in many neuronal cell types. In various cell types, membrane excitability is mainly controlled by being the only persistent current in the range of action potential firing (Marrion Annual Review Physiology 1997, 59, 483-504). The modulation of the M-current has a great influence on the excitability of neurons, for example, the activation of the current will reduce the excitability of neurons. Openers of these KCNQ channels or activators of M-currents will reduce excessive neuronal activity and thus can be used to treat, prevent or inhibit epileptic seizures and other diseases and disorders characterized by excessive neuronal activity, such as neuronal hyperactivity. Excitability includes convulsions, seizures, and neuropathic pain.

EP 554543公开了瑞替加滨(D-23129；N-(2-氨基-4-(4-氟苄基氨基)-苯基)氨基甲酸乙酯)及其类似物。在体内和体外瑞替加滨均为广谱并具有有效抗惊厥特性的抗惊厥化合物。对大鼠和小鼠口服给药和腹膜内给药后，其在一系列抗惊厥试验和遗传动物模型(DBA/2小鼠，Rostock等人，Epilepsy Research 1996，23，211-223)中为有效的，这些抗惊厥试验包括：电诱导的癫痫；戊四氮、印防己毒素和N-甲基-D-天冬氨酸盐(NMDA)化学诱导的癫痫。此外，瑞替加滨在复杂的不完全癫痫的杏仁核癫痫(amygdala kindling)模型中有效，这还表明该化合物可用于抗惊厥治疗。在临床试验中，最近已表明瑞替加滨能有效减少癫痫病人发作的机会(Bialer等人，Epilepsy Research2002，51，31-71)。EP 554543 discloses retigabine (D-23129; ethyl N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamate) and analogs thereof. Retigabine is a broad-spectrum anticonvulsant compound with potent anticonvulsant properties both in vivo and in vitro. After oral administration and intraperitoneal administration to rats and mice, it was effective in a series of anticonvulsant tests and genetic animal models (DBA/2 mice, Rostock et al., Epilepsy Research 1996, 23, 211-223). Available, these anticonvulsant tests include: electrically induced epilepsy; chemically induced epilepsy with pentetrazol, picrotoxin, and N-methyl-D-aspartate (NMDA). In addition, retigabine was effective in a model of amygdala kindling with complex incomplete epilepsy, which also suggests that the compound may be useful in anticonvulsant therapy. In clinical trials, retigabine has recently been shown to be effective in reducing the chance of seizures in epilepsy patients (Bialer et al., Epilepsy Research 2002, 51, 31-71).

已表明瑞替加滨活化神经元细胞中的K(+)电流，这种感应电流的药理学表明与公开的M-通道的药理学一致，M-通道最近被发现与KCNQ2/3K(+)通道异源多聚体(heteromultimer)相关。这表明KCNQ2/3通道的活化可能导致该试剂的某些抗惊厥活性(Wickenden等人，Molecular Pharmacology 2000，58，591-600)，并且其他通过相同的机理作用的试剂可能具有相同的用途。Retigabine has been shown to activate K(+) currents in neuronal cells, and the pharmacology of this induced current is consistent with the published pharmacology of M-channels, which were recently discovered to associate with KCNQ2/3K(+) Channel heteromultimers are associated. This suggests that activation of KCNQ2/3 channels may be responsible for some of the anticonvulsant activity of this agent (Wickenden et al., Molecular Pharmacology 2000, 58, 591-600), and that other agents acting by the same mechanism may have the same utility.

已报道KCNQ2和3通道用于调节(upregulate)神经痛模型(Wickenden等人，Society for Neuroscience Abstracts 2002，454.7)，且假设钾通道调节剂对于神经痛和癫痫均有活性(Schroder等人，Neuropharmacology 2001，40，888-898)。KCNQ2 and 3 channels have been reported to upregulate models of neuralgia (Wickenden et al., Society for Neuroscience Abstracts 2002, 454.7), and potassium channel modulators are hypothesized to be active in both neuralgia and epilepsy (Schroder et al., Neuropharmacology 2001 , 40, 888-898).

也已表明瑞替加滨对于神经痛的动物模型有效(Blackburn-Munro和Jensen European Journal of Pharmacology 2003，460，109-116)，因此建议KCNQ通道的开放剂用于治疗包括神经痛的疼痛疾病。Retigabine has also been shown to be effective in animal models of neuralgia (Blackburn-Munro and Jensen European Journal of Pharmacology 2003, 460, 109-116), thus suggesting KCNQ channel openers for the treatment of pain disorders including neuralgia.

据报道KCNQ通道mRNA集中于脑部和其他与疼痛相关的中枢神经系统(Goldstein等，Society for Neuroscience Abstracts 2003，53.8)。KCNQ channel mRNA is reported to be localized in the brain and other pain-related central nervous systems (Goldstein et al., Society for Neuroscience Abstracts 2003, 53.8).

除了在神经疼痛中的作用，在三叉神经和背根神经节以及在尾侧三叉神经核中的KCNQ2-5的mRNA的表达表明这些通道的开放剂还可影响偏头痛的感觉过程(Goldstein等人，Society for NeuroscienceAbstracts 2003，53.8)。In addition to a role in neuropathic pain, mRNA expression of KCNQ2-5 in the trigeminal and dorsal root ganglia as well as in the caudal trigeminal nucleus suggests that openers of these channels may also affect sensory processes in migraine (Goldstein et al. , Society for Neuroscience Abstracts 2003, 53.8).

最近报道证明KCNQ3和5以及KCNQ2的mRNA表达于蛛形细胞和神经胶质细胞中。因此KCNQ2、3和5通道可助于调节中枢神经系统中的突触活性，并且有助于KCNQ通道开放剂的中性保护作用(Noda等人，Society for Neuroscience Abstracts 2003，53.9)。Recent reports demonstrated that the mRNAs of KCNQ3 and 5, as well as KCNQ2, are expressed in arachnoid cells and glial cells. KCNQ2, 3 and 5 channels may thus contribute to the regulation of synaptic activity in the central nervous system and contribute to the neutral protective effect of KCNQ channel openers (Noda et al., Society for Neuroscience Abstracts 2003, 53.9).

因此瑞替加滨和其他KCNQ调节剂可保护避免癫痫症的神经变性，因为已表明瑞替加滨防止缘神经变性以及大鼠体内海人酸诱发的癫痫后编程性细胞死亡的标记表达(Ebert等人，Epilepsia 2002，43增补5，86-95)。这可防止病人癫痫的发作，即抗癫痫。在癫痫研究的另一个模型中，已表明瑞替加滨延迟大鼠体内的海马癫痫的发作(Tober等人，European Journal of Pharmacology 1996，303，163-169)。Thus retigabine and other KCNQ modulators may protect against neurodegeneration in epilepsy, as retigabine has been shown to prevent limbic nerve degeneration and expression of markers of apoptosis after kainic acid-induced epilepsy in rats (Ebert et al. et al., Epilepsia 2002, 43 Suppl. 5, 86-95). This prevents the patient's seizures, known as antiepileptics. In another model of epilepsy research, retigabine has been shown to delay the onset of hippocampal epilepsy in rats (Tober et al., European Journal of Pharmacology 1996, 303, 163-169).

因此表明瑞替加滨和其他KCNQ调节剂的这些性质可预防由过度神经活化诱发的神经损伤，并可用于治疗神经病变的疾病，并为癫痫患者的疾病缓和(modifying)(或抗癫痫)剂。These properties of retigabine and other KCNQ modulators therefore suggest that they may prevent neural damage induced by excessive neural activation and may be useful in the treatment of neuropathic diseases and as disease modifying (or antiepileptic) agents in epileptic patients .

在已知抗惊厥化合物(例如苯并二氮杂和氯甲基噻唑(chlorme-thiazole))用于临床治疗戒除乙醇综合症以及其他抗惊厥化合物(例如加巴喷丁)(Watson等人，Neuropharmacology 1997，36，1369-1375)在这种综合症的动物模型中非常有效的条件下，我们预期其他抗惊厥化合物(如KCNQ开放剂)也可有效地用于这种疾病。Known anticonvulsant compounds such as benzodiazepines and chlorme-thiazole are used clinically in the treatment of alcohol withdrawal syndrome as well as other anticonvulsant compounds such as gabapentin (Watson et al., Neuropharmacology 1997, 36, 1369-1375) are very effective in animal models of this syndrome, we expect that other anticonvulsant compounds such as KCNQ openers will also be effective in this disease.

KCNQ2和3亚型的mRNA发现于与焦虑和情绪行为(例如两极性疾病，如海马和杏仁核)有关的脑部区域(Saganich等人，Journal ofNeuroscience 2001，21，4609-4624)，据报道瑞替加滨在焦虑类行为的某些动物模型中有活性(Hartz等人，Journal of Psychopharmacology 2003，17增补3，A28，B16)，并且其他临床使用的抗惊厥化合物用于治疗两极性疾病。The mRNAs for KCNQ2 and 3 isoforms are found in brain regions associated with anxiety and emotional behavior (e.g., bipolar disorders, such as the hippocampus and amygdala) (Saganich et al., Journal of Neuroscience 2001, 21, 4609-4624), as reported by Ray Tigabine is active in some animal models of anxiety-like behavior (Hartz et al., Journal of Psychopharmacology 2003, 17 Suppl. 3, A28, B16), and other clinically used anticonvulsant compounds for the treatment of bipolar disorders.

WO 200196540公开了KCNQ2和KCNQ3基因表达形成的M-电流的调节剂治疗失眠的用途，而WO 2001092526公开了KCNQ5的调节剂可用于治疗睡眠障碍。WO 200196540 discloses the use of regulators of M-current formed by KCNQ2 and KCNQ3 gene expression to treat insomnia, while WO 2001092526 discloses that regulators of KCNQ5 can be used to treat sleep disorders.

WO01/022953描述了瑞替加滨用于预防和治疗神经痛，如异常性疼痛、痛觉过敏性疼痛、幻痛、与糖尿病性神经病相关的神经痛以及与偏头痛相关的神经痛。WO 01/022953 describes retigabine for the prophylaxis and treatment of neuralgia such as allodynia, hyperalgesic pain, phantom pain, neuralgia associated with diabetic neuropathy and neuralgia associated with migraine.

WO02/049628描述了瑞替加滨用于预防、治疗、抑制和缓解焦虑疾病的用途，例如焦虑、广泛性焦虑症、恐慌性焦虑症、强迫观念与行为症、社会恐怖、行为焦虑、创伤后应激症、急性应激反应、适应性障碍、疑病症、分离焦虑症、广场恐怖症和特异性恐怖症。WO02/049628 describes the use of retigabine for the prevention, treatment, suppression and alleviation of anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety disorder, obsessive-compulsive disorder, social phobia, behavioral anxiety, post-traumatic Stress disorder, acute stress response, adjustment disorder, hypochondriac disorder, separation anxiety disorder, agoraphobia, and specific phobia.

WO97/15300描述了瑞替加滨用于治疗神经变性疾病的用途，例如阿尔茨海默氏病、亨廷顿舞蹈病、硬化症如多发性硬化和肌萎缩性侧索硬化症；克罗伊茨费尔特-雅各布病、帕金森氏病、AIDS-诱发的脑病以及由风疹病毒、疱疹病毒、疏螺旋体属以及未知病原体感染引起的脑病、外伤引起的神经变性以及在药物戒毒过程或由于醉酒引起的神经元兴奋过度状态、周围神经系统的变性疾病(如多神经病和多神经炎(polyneuritides))。WO97/15300 describes the use of retigabine for the treatment of neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, sclerosis such as multiple sclerosis and amyotrophic lateral sclerosis; Gert-Jakob disease, Parkinson's disease, AIDS-induced encephalopathy and encephalopathy caused by infection with rubella virus, herpes virus, Borrelia and unknown pathogens, neurodegeneration caused by trauma and during drug withdrawal or due to intoxication Hyperexcitatory state of neurons, degenerative diseases of the peripheral nervous system (such as polyneuropathy and polyneuritis (polyneuritis)).

因此，对作为KCNQ家族钾通道有效开放剂的新型化合物有很大的需求。Therefore, there is a great need for novel compounds that are potent openers of potassium channels of the KCNQ family.

还需要与作为KCNQ家族钾通道开放剂的已知化合物(例如瑞替加滨)相比，具有改进的性能的新型化合物。需要改进一种或多种以下参数：半衰期、清除率、选择性、与其他药物的相互作用、生物可利用率、效能、可调配性、化学稳定性、新陈代谢稳定性、膜渗透性、溶解度以及治疗指数。这些参数的改进导致如下的改善：There is also a need for new compounds with improved properties compared to known compounds that are potassium channel openers of the KCNQ family, such as retigabine. One or more of the following parameters need to be improved: half-life, clearance, selectivity, interaction with other drugs, bioavailability, potency, formulatability, chemical stability, metabolic stability, membrane permeability, solubility, and therapeutic index. Improvement of these parameters resulted in the following improvements:

●通过减少每天所需给药次数来改进给药方案，Improving dosing regimens by reducing the number of doses required per day,

●通过多种给药法便于对病人给药，●It is convenient to administer medicines to patients through a variety of administration methods,

●减少副作用，●Reduce side effects,

●增加治疗指数，● increase the therapeutic index,

●提高耐受性，或●Improved tolerance, or

●提高顺应性(compliance)。●Improve compliance.

                    发明概述Invention Summary

本发明的一个目的为提供新型化合物，所述化合物为KCNQ家族钾离子通道有效的开放剂。One object of the present invention is to provide novel compounds which are potent openers of KCNQ family potassium ion channels.

本发明的化合物为通式I的取代的二氢吲哚和吲哚衍生物或其盐：The compounds of the present invention are substituted indoline and indole derivatives of general formula I or salts thereof:

Figure A20048001101900251
Figure A20048001101900251

其中虚线、q、s、U、Y、X、Z、R1、R1’、R2和R3如下定义。本发明还涉及包含式I化合物的药物组合物及其用途。wherein dashed line, q, s, U, Y, X, Z, R 1 , R 1′ , R 2 and R 3 are defined as follows. The present invention also relates to pharmaceutical compositions comprising compounds of formula I and uses thereof.

                      发明描述Invention Description

因此，本发明涉及通式I的取代的吲哚和二氢吲哚衍生物或其盐，Accordingly, the present invention relates to substituted indole and indoline derivatives of general formula I or salts thereof,

Figure A20048001101900261
Figure A20048001101900261

其中in

虚线表示任选的键；Dashed lines indicate optional bonds;

R1和R1’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；或R 1 and R 1' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-C 3-8 -cycloalkane (en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo Substitute-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; or

R1和R1’与其连接的碳原子一起形成3至8元饱和或不饱和环，所述环任选包含1或2个杂原子；R 1 and R 1' together with the carbon atoms to which they are attached form a 3 to 8 membered saturated or unsaturated ring, said ring optionally comprising 1 or 2 heteroatoms;

s为0或1；s is 0 or 1;

U为O、NR11、S、SO2、SO2NR11、CO-O或CO-NR11；其中R11选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；或R2和R11与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子；U is O, NR 11 , S, SO 2 , SO 2 NR 11 , CO-O or CO-NR 11 ; wherein R 11 is selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; or R 2 and R 11 together form a 4 to 8 membered A saturated or unsaturated ring optionally comprising 1, 2 or 3 other heteroatoms;

R2选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、酰基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤素、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、-NO2、NR10R10’-C1-6-烷(烯/炔)基、NR10R10’-C3-8-环烷(烯)基和NR10R10’-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；R 2 is selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk( En/alkyn)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-C 3-8 -cycloalkane (en)yl-C 1-6 -alk(en/yn)yl, acyl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy -C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halogen, halo-C 1-6 -alk(en/yn)yl, halo-C 3- 8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano, cyano-C 1-6 -alk( En/alkynyl) group, cyano-C 3-8 -cycloalk(en)yl, cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, - NO 2 , NR 10 R 10' -C 1-6 -alk(en/yn)yl, NR 10 R 10' -C 3-8 -cycloalk(en)yl and NR 10 R 10' -C 3-8 -Cycloalk(en)yl-C 1-6 -alk(en/yn)yl;

其中in

R10和R10’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3- 8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基，或R 10 and R 10' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-C 3-8 -cycloalkane (en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo Substitute-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, or

R10和R10’与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子；R 10 and R 10' together with the nitrogen atom to which they are attached form a 4 to 8 membered saturated or unsaturated ring, which ring optionally contains 1, 2 or 3 other heteroatoms;

条件是当R2为NO2、卤素或氰基时，s为0；和with the proviso that when R2 is NO2 , halo or cyano, s is 0; and

条件是当R2为氢原子或酰基且s为1时，U为NR11、O或S；The proviso is that when R 2 is a hydrogen atom or an acyl group and s is 1, U is NR 11 , O or S;

其中基团-(U)s-R2连接在吲哚或二氢吲哚的4或6位；Wherein the group -(U) s -R 2 is connected to the 4 or 6 position of indole or indoline;

q为0或1；q is 0 or 1;

Z为O或S；Z is O or S;

X为CO或SO2；条件是当X为SO2时，q为0；X is CO or SO 2 ; the condition is that when X is SO 2 , q is 0;

R3选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、杂环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、C1-6-烷(烯/炔)基-杂环烷(烯)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-杂环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基-C1-6-烷(烯/炔)基-杂环烷(烯)基、C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基氧基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基氧基-C3-8-环烷(烯)基、C1-6-烷(烯/炔)基氧基-杂环烷(烯)基、芳基-氧基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基氧基-羰基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基氧基-羰基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基氧基-羰基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-杂环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、羟基-C1-6-烷(烯/炔)基-杂环烷(烯)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-杂环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、卤代-C1-6-烷(烯/炔)基-杂环烷(烯)基、卤代-C1- 6-烷(烯/炔)基-芳基、卤代-C3-8-环烷(烯)基-芳基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基-芳基、卤代-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基-芳基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-杂环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、氰基-C1-6-烷(烯/炔)基-杂环烷(烯)基、酰基-C1-6-烷(烯/炔)基、酰基-C3-8-环烷(烯)基、酰基-杂环烷(烯)基、酰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、酰基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、酰基-C1-6-烷(烯/炔)基-杂环烷(烯)基和-NR12R12’、任选取代的NR12R12’-C1-6-烷(烯/炔)基、任选取代的NR12R12’-C3-8-环烷(烯)基、任选取代的NR12R12’-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；其中R 3 is selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, heterocycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, C 1-6 -alk(en/yn)yl- Heterocycloalk(en)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-heterocycloalk(en)yl ) group, aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl-C 3- 8 -cycloalk(en)yl, aryl-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, C 1-6 -alk(en/yn)yloxy-C 1 -6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yloxy-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl Oxy-C 3-8 -cycloalk(en)yl, C 1-6 -alk(en/yn)yloxy-heterocycloalk(en)yl, aryl-oxy-C 1-6 -alk (en/yn)yl, aryl-C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl Oxy-carbonyl-C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn) Alkynyl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en) /alkynyl) group, hydroxy-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, hydroxy-C 1-6 -alk(en/yn)yl-heterocycloalkane (en)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-heterocycloalk(en)yl, halo- C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en) ) group, halo-C 1-6 -alk(en/yn)yl-heterocycloalkane(en)yl, halo-C 1-6 -alk(en/yn)yl-aryl, halo-C 3-8 -cycloalk(en)yl-aryl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl-aryl, halo-C 1 -6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl-aryl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8- Cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, cyano-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, acyl- C 1-6 -alk(en/yn)yl, acyl-C 3-8 -cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C 3-8 -cycloalk(en)yl -C 1-6 -alk(en/yn)yl, acyl-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, acyl-C 1-6 -alk( En/alkyn)yl-heterocycloalkan(en)yl and -NR 12 R 12' , optionally substituted NR 12 R 12' -C 1-6 -alk(en/yn)yl, optionally substituted NR 12 R 12' -C 3-8 -cycloalk(en)yl, optionally substituted NR 12 R 12' -C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl ;in

R12和R12’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3- 8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基，或R 12 and R 12' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en) ) group, hydroxyl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en) /alkynyl), cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, or

R12和R12’与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子；R 12 and R 12' together with the nitrogen atom to which they are attached form a 4 to 8 membered saturated or unsaturated ring, which ring optionally contains 1, 2 or 3 other heteroatoms;

条件是当R3为NR12R12’时，q为0；The condition is that when R 3 is NR 12 R 12' , q is 0;

和and

Y表示式II、III、IV、V、VI、XXX和XXXI的基团：Y represents a group of formulas II, III, IV, V, VI, XXX and XXXI:

Figure A20048001101900291
Figure A20048001101900291

或or

Figure A20048001101900292
Figure A20048001101900292

其中in

直线表示将Y所示的基团与碳原子连接的键；The straight line represents the bond connecting the group represented by Y to the carbon atom;

W为O或S；W is O or S;

T为N、NH或O；T is N, NH or O;

L为N、C或CH；L is N, C or CH;

a为0、1、2或3；a is 0, 1, 2 or 3;

b为0、1、2、3或4；b is 0, 1, 2, 3 or 4;

c为0或1；c is 0 or 1;

d为0、1、2或3；d is 0, 1, 2 or 3;

e为0、1或2；e is 0, 1 or 2;

f为0、1、2、3、4或5；f is 0, 1, 2, 3, 4 or 5;

g为0、1、2、3或4；g is 0, 1, 2, 3 or 4;

h为0、1、2或3；h is 0, 1, 2 or 3;

j为0、1、2或3；条件是当T为氮原子时，j为0、1、2或3；和当T为NH或氧原子时，j为0、1或2；j is 0, 1, 2 or 3; provided that when T is a nitrogen atom, j is 0, 1, 2 or 3; and when T is NH or an oxygen atom, j is 0, 1 or 2;

k为0、1、2、3或4；且k is 0, 1, 2, 3 or 4; and

R5各自独立地选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-硫基、芳基-氧基、酰基、C1-6-烷(烯/炔)基氧基、C3-8-环烷(烯)基氧基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基氧基、卤素、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、-CO-NR6R6’、氰基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、-NR7R7’、-S-R8和-SO2R8，或两个相邻的R5与其连接的芳基一起形成任选包含一个或两个杂原子的4至8元环；R 5 are each independently selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk (en/yn)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-thio, aryl-oxy, acyl, C 1-6 -alk(en/yn) )yloxy, C 3-8 -cycloalk(en)yloxy, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy, halogen, halo -C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk (en/yn)yl, -CO-NR 6 R 6' , cyano, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl, Cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, -NR 7 R 7' , -SR 8 and -SO 2 R 8 , or two adjacent R together with the aryl to which it is attached forms a 4 to 8 membered ring optionally containing one or two heteroatoms;

R6和R6’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基和芳基；R 6 and R 6' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl and aryl;

R7和R7’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基和酰基；R 7 and R 7' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl and acyl;

和and

R8选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基和-NR9R9’；其中R9和R9’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基和C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；条件是当R8为-NR9R9’时，R5不为-S-R8。R 8 is selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk( En/alkyn) base, aryl and -NR 9 R 9' ; wherein R 9 and R 9' are independently selected from hydrogen, C 1-6 -alk(en/alkyn) group, C 3-8 -cycloalkane ( alken)yl and C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; with the proviso that when R 8 is -NR 9 R 9' , R 5 is not -SR 8 .

本发明的一个特别的实施方案涉及通式I的取代的吲哚和二氢吲哚衍生物及其盐，A particular embodiment of the invention relates to substituted indole and indoline derivatives of general formula I and salts thereof,

Figure A20048001101900311
Figure A20048001101900311

其中in

虚线表示任选的键；Dashed lines indicate optional bonds;

R1和R1’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；或R 1 and R 1' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-C 3-8 -cycloalkane (en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo Substitute-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; or

R1和R1’形成3至8元饱和或不饱和环，所述环任选包含1或2个其他杂原子；R 1 and R 1' form a 3 to 8 membered saturated or unsaturated ring, said ring optionally comprising 1 or 2 other heteroatoms;

s为0或1；s is 0 or 1;

U为O、NR11、S、SO2、SO2NR11、CO-O或CO-NR11；其中R11选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；或U is O, NR 11 , S, SO 2 , SO 2 NR 11 , CO-O or CO-NR 11 ; wherein R 11 is selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; or

R2和R11与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子；R and R together with the nitrogen atom to which they are attached form a 4 to 8 membered saturated or unsaturated ring, which ring optionally contains 1, 2 or 3 other heteroatoms;

R2选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、酰基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤素、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、-NO2、NR10R10’-C1-6-烷(烯/炔)基、NR10R10’-C3-8-环烷(烯)基和NR10R10’-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；R 2 is selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk( En/alkyn)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-C 3-8 -cycloalkane (en)yl-C 1-6 -alk(en/yn)yl, acyl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy -C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halogen, halo-C 1-6 -alk(en/yn)yl, halo-C 3- 8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano, cyano-C 1-6 -alk( En/alkynyl) group, cyano-C 3-8 -cycloalk(en)yl, cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, - NO 2 , NR 10 R 10' -C 1-6 -alk(en/yn)yl, NR 10 R 10' -C 3-8 -cycloalk(en)yl and NR 10 R 10' -C 3-8 -Cycloalk(en)yl-C 1-6 -alk(en/yn)yl;

其中in

R10和R10’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3- 8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基，或R 10 and R 10' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-C 3-8 -cycloalkane (en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo Substitute-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, or

R10和R10’与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子；R 10 and R 10' together with the nitrogen atom to which they are attached form a 4 to 8 membered saturated or unsaturated ring, which ring optionally contains 1, 2 or 3 other heteroatoms;

条件是当R2为NO2、卤素或氰基时，s为0；和with the proviso that when R2 is NO2 , halo or cyano, s is 0; and

条件是当R2为氢原子或酰基且s为1时，U为NR11、O或S；The proviso is that when R 2 is a hydrogen atom or an acyl group and s is 1, U is NR 11 , O or S;

其中基团-(U)s-R2连接在吲哚或二氢吲哚的4或6位；Wherein the group -(U) s -R 2 is connected to the 4 or 6 position of indole or indoline;

q为0或1；q is 0 or 1;

Z为O或S；Z is O or S;

X为CO或SO2；条件是当X为SO2时，q为0；X is CO or SO 2 ; the condition is that when X is SO 2 , q is 0;

R3选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、杂环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、C1-6-烷(烯/炔)基-杂环烷(烯)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-杂环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基-C1-6-烷(烯/炔)基-杂环烷(烯)基、C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基氧基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基氧基-C3-8-环烷(烯)基、C1-6-烷(烯/炔)基氧基-杂环烷(烯)基、芳基-氧基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基氧基-羰基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基氧基-羰基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基氧基-羰基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-杂环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、羟基-C1-6-烷(烯/炔)基-杂环烷(烯)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代杂环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、卤代-C1-6-烷(烯/炔)基-杂环烷(烯)基、卤代-C1- 6-烷(烯/炔)基-芳基、卤代-C3-8-环烷(烯)基-芳基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基-芳基、卤代-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基-芳基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-杂环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、氰基-C1-6-烷(烯/炔)基-杂环烷(烯)基、酰基-C1-6-烷(烯/炔)基、酰基-C3-8-环烷(烯)基、酰基-杂环烷(烯)基、酰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、酰基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、酰基-C1-6-烷(烯/炔)基-杂环烷(烯)基和-NR12R12’；其中R 3 is selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, heterocycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, C 1-6 -alk(en/yn)yl- Heterocycloalk(en)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-heterocycloalk(en)yl ) group, aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl-C 3- 8 -cycloalk(en)yl, aryl-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, C 1-6 -alk(en/yn)yloxy-C 1 -6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yloxy-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl Oxy-C 3-8 -cycloalk(en)yl, C 1-6 -alk(en/yn)yloxy-heterocycloalk(en)yl, aryl-oxy-C 1-6 -alk (en/yn)yl, aryl-C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl Oxy-carbonyl-C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn) Alkynyl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en) /alkynyl) group, hydroxy-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, hydroxy-C 1-6 -alk(en/yn)yl-heterocycloalkane (en)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-heterocycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en) Base, halo-C 1-6 -alk(en/yn)yl-heterocycloalkane(en)yl, halo-C 1-6 -alk(en/yn)yl-aryl, halo-C 3 -8 -cycloalk(en)yl-aryl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl-aryl, halo-C 1- 6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl-aryl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cyclo Alk(en)yl, cyano-heterocycloalk(en)yl, cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1 -6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, cyano-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, acyl-C 1-6 -alk(en/yn)yl, acyl-C 3-8 -cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C 3-8 -cycloalk(en)yl- C 1-6 -alk(en/yn)yl, acyl-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, acyl-C 1-6 -alk(en)yl /alkyn) base-heterocycloalkane (en) base and -NR 12 R 12' ; where

R12和R12’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3- 8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基，或R 12 and R 12' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en) ) group, hydroxyl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en) /alkynyl), cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, or

R12和R12’与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子；R 12 and R 12' together with the nitrogen atom to which they are attached form a 4 to 8 membered saturated or unsaturated ring, which ring optionally contains 1, 2 or 3 other heteroatoms;

条件是当R3为NR12R12’时，q为0；The condition is that when R 3 is NR 12 R 12' , q is 0;

和and

Y表示式II、III、IV、V和VI的基团：Y represents a group of formulas II, III, IV, V and VI:

或

Figure A20048001101900342
or
Figure A20048001101900342

其中in

直线表示将Y所示基团与碳原子连接的键；The straight line represents the bond connecting the group represented by Y to the carbon atom;

W为O或S；W is O or S;

a为0、1、2或3；a is 0, 1, 2 or 3;

b为0、1、2、3或4；b is 0, 1, 2, 3 or 4;

c为0或1；c is 0 or 1;

d为0、1、2或3；d is 0, 1, 2 or 3;

e为0、1或2；e is 0, 1 or 2;

f为0、1、2、3、4或5；f is 0, 1, 2, 3, 4 or 5;

g为0、1、2、3或4；g is 0, 1, 2, 3 or 4;

h为0、1、2或3；和h is 0, 1, 2 or 3; and

R5各自独立地选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-C1-6-烷(烯/炔)基、酰基、C1-6-烷(烯/炔)基氧基、C3-8-环烷(烯)基氧基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基氧基、卤素、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、-CO-NR6R6’、氰基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、-NR7R7’、-S-R8和-SO2R8，或R 5 are each independently selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk (en/yn)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, acyl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalkane (en)yloxy, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy, halogen, halo-C 1-6 -alk(en/yne) Halo-C 3-8 -cycloalk(en)yl, Halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, -CO-NR 6 R 6' , cyano, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl, cyano-C 3-8 -cycloalk(en)yl ) group-C 1-6 -alk(en/yn)yl, -NR 7 R 7' , -SR 8 and -SO 2 R 8 , or

两个相邻的R5与其连接的芳基一起形成任选包含一个或两个杂原子的4至8元环；Two adjacent R 's together with the aryl to which they are attached form a 4 to 8 membered ring optionally containing one or two heteroatoms;

R6和R6’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基和芳基；R 6 and R 6' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl and aryl;

R7和R7’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基和酰基；R 7 and R 7' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl and acyl;

和and

R8选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基和-NR9R9’；其中R 8 is selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk( En/alkyn) base, aryl and -NR 9 R 9' ; Wherein

R9和R9’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基和C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；R 9 and R 9' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl and C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl;

条件是当R8为-NR9R9’时，R5不为-S-R8。The proviso is that when R 8 is -NR 9 R 9' , R 5 is not -SR 8 .

本发明的一个实施方案涉及式I化合物，其中虚线表示键。One embodiment of the invention relates to compounds of formula I, wherein the dashed lines represent bonds.

本发明的另一个实施方案涉及式I化合物，其中虚线不表示键。Another embodiment of the present invention relates to compounds of formula I, wherein the dashed lines do not indicate bonds.

本发明的又一个实施方案涉及式I化合物，其中R1和R1’独立地选自羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基。Yet another embodiment of the present invention relates to compounds of formula I, wherein R 1 and R 1' are independently selected from hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalkane(en) Hydroxy-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3 -8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/ Alkynyl, cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl.

本发明的另一个实施方案涉及式I化合物，其中R1和R1’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基和C3-8-环烷(烯)基-C1-6-烷(烯/炔)基。Another embodiment of the present invention relates to compounds of formula I, wherein R and R are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl and C 3-8 -Cycloalk(en)yl-C 1-6 -alk(en/yn)yl.

本发明的又一个实施方案涉及式I化合物，其中R1和R1’形成3至8元饱和或不饱和环，所述环任选包含1或2个杂原子。在又一个实施方案中所述3至8元饱和或不饱和环为饱和碳环，通常为环丙基、环丁基、环戊基或环己基。Yet another embodiment of the present invention relates to compounds of formula I, wherein R 1 and R 1′ form a 3 to 8 membered saturated or unsaturated ring, said ring optionally comprising 1 or 2 heteroatoms. In yet another embodiment the 3 to 8 membered saturated or unsaturated ring is a saturated carbocycle, typically cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

本发明的再一个实施方案涉及式I化合物，其中R1和R1’独立地选自氢原子和C1-6-烷(烯/炔)基。Yet another embodiment of the present invention relates to compounds of formula I, wherein R 1 and R 1' are independently selected from a hydrogen atom and a C 1-6 -alk(en/yn)yl group.

在再一个实施方案中，本发明涉及式I化合物，其中R1和R1’中至少一个为C1-6-烷(烯/炔)基，通常为C1-3-烷(烯/炔)基。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one of R 1 and R 1' is C 1-6 -alk(en/yn)yl, typically C 1-3 -alk(en/yne) )base.

在一个优选实施方案中，本发明涉及式I化合物，其中R1或R1’为氢原子。In a preferred embodiment, the invention relates to compounds of formula I, wherein R 1 or R 1′ is a hydrogen atom.

在一个优选实施方案中，本发明涉及式I化合物，其中R1和R1’中至少一个为氢原子。In a preferred embodiment, the invention relates to compounds of formula I, wherein at least one of R 1 and R 1′ is a hydrogen atom.

在一个更优选实施方案中，本发明涉及式I化合物，其中R1和R1’都为氢原子。In a more preferred embodiment, the invention relates to compounds of formula I, wherein R 1 and R 1' are both hydrogen atoms.

在一个优选实施方案中，本发明涉及式I化合物，其中s为0。In a preferred embodiment, the invention relates to compounds of formula I, wherein s is 0.

在另一个优选实施方案中，本发明涉及式I化合物，其中s为1。In another preferred embodiment, the invention relates to compounds of formula I, wherein s is 1 .

在一个实施方案中，本发明涉及式I化合物，其中s为1且U为O。In one embodiment, the invention relates to compounds of formula I, wherein s is 1 and U is O.

在另一个实施方案中，本发明涉及式I化合物，其中s为1且U为S。In another embodiment, the invention relates to compounds of formula I, wherein s is 1 and U is S.

在再一个实施方案中，本发明涉及式I化合物，其中s为1且U为SO2。In yet another embodiment, the invention relates to compounds of formula I, wherein s is 1 and U is SO2 .

在再一个实施方案中，本发明涉及式I化合物，其中s为1且U为SO2NR11。In yet another embodiment, the invention relates to compounds of formula I, wherein s is 1 and U is SO 2 NR 11 .

在再一个实施方案中，本发明涉及式I化合物，其中s为1且U为CO-O。In yet another embodiment, the invention relates to compounds of formula I, wherein s is 1 and U is CO-O.

在再一个实施方案中，本发明涉及式I化合物，其中s为1且U为CO-NR11。In yet another embodiment, the invention relates to compounds of formula I, wherein s is 1 and U is CO-NR 11 .

在一个优选实施方案中，本发明涉及式I化合物，其中s为1且U为NR11。In a preferred embodiment, the invention relates to compounds of formula I, wherein s is 1 and U is NR 11 .

在再一个实施方案中，本发明涉及式I化合物，其中s为1，U为SO2NR11、CO-NR11或NR11且R11为氢原子。In yet another embodiment, the invention relates to compounds of formula I, wherein s is 1, U is SO2NR11 , CO- NR11 or NR11 and R11 is a hydrogen atom.

在一个优选实施方案中，本发明涉及式I化合物，其中s为1，U为NR11且R11为氢原子。In a preferred embodiment, the invention relates to compounds of formula I, wherein s is 1, U is NR 11 and R 11 is a hydrogen atom.

本发明的一个实施方案涉及式I化合物，其中R2选自酰基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、NR10R10’-C1-6-烷(烯/炔)基、NR10R10’-C3-8-环烷(烯)基和NR10R10’-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；One embodiment of the present invention relates to compounds of formula I, wherein R 2 is selected from the group consisting of acyl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalkane (en)yl, cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, NR 10 R 10' -C 1-6 -alk(en/yn) NR 10 R 10' -C 3-8 -cycloalk(en)yl and NR 10 R 10' -C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl ;

条件是当R2为酰基且s为1时，U为NR11、O或S。with the proviso that when R2 is acyl and s is 1, U is NR11 , O or S.

本发明的另一个实施方案涉及式I化合物，其中R2选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基和C3-8-环烷(烯)基-C1-6-烷(烯/炔)基。Another embodiment of the present invention relates to compounds of formula I, wherein R 2 is selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl and C 3-8 -cycloalkane ( En)yl-C 1-6 -alk(en/yn)yl.

本发明的再一个实施方案涉及式I化合物，其中R2选自芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基和芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基。Yet another embodiment of the present invention relates to compounds of formula I, wherein R is selected from aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl and aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl.

本发明的再一个实施方案涉及式I化合物，其中R2选自卤素、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基和氰基；Yet another embodiment of the present invention relates to compounds of formula I, wherein R 2 is selected from halogen, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, Halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl and cyano;

条件是当R2为卤素或氰基时，s为0。with the proviso that when R2 is halo or cyano, s is 0.

在一个优选实施方案中，本发明涉及式I化合物，其中R2为NO2或氢原子；In a preferred embodiment, the present invention relates to compounds of formula I, wherein R 2 is NO 2 or a hydrogen atom;

条件是当R2为NO2时，s为0；和with the proviso that when R2 is NO2 , s is 0; and

条件是当R2为氢原子且s为1时，U为NR11、O或S。The proviso is that when R 2 is a hydrogen atom and s is 1, U is NR 11 , O or S.

在一个实施方案中，本发明涉及式I化合物，其中R2为NO2、氢原子或卤原子；In one embodiment, the present invention relates to compounds of formula I, wherein R 2 is NO 2 , a hydrogen atom or a halogen atom;

条件是当R2为NO2或卤原子时，s为0；和with the proviso that when R2 is NO2 or a halogen atom, s is 0; and

条件是当R2为氢原子且s为1时，U为NR11、O或S。The proviso is that when R 2 is a hydrogen atom and s is 1, U is NR 11 , O or S.

在另一个实施方案中，本发明涉及式I化合物，其中s为0且R2为NO2或卤原子。In another embodiment, the invention relates to compounds of formula I, wherein s is 0 and R2 is NO2 or a halogen atom.

在一个实施方案中，本发明涉及式I化合物，其中R2为氢原子。In one embodiment, the invention relates to compounds of formula I, wherein R 2 is a hydrogen atom.

在一个实施方案中，本发明涉及式I化合物，其中s为0且R2选自NO2、卤素和氰基。In one embodiment, the invention relates to compounds of formula I, wherein s is 0 and R2 is selected from NO2 , halogen and cyano.

在另一个实施方案中，本发明涉及式I化合物，其中s为0且R2为氢原子。In another embodiment, the invention relates to compounds of formula I, wherein s is 0 and R2 is a hydrogen atom.

在再一个实施方案中，本发明涉及式I化合物，其中R2为C1-6-烷(烯/炔)基，通常为C1-3-烷(烯/炔)基。In yet another embodiment, the invention relates to compounds of formula I, wherein R 2 is C 1-6 -alk(en/yn)yl, typically C 1-3 -alk(en/yn)yl.

在再一个实施方案中，本发明涉及式I化合物，其中R2为C3-8-环烷(烯)基，通常为C3-6-环烷(烯)基。In yet another embodiment, the invention relates to compounds of formula I, wherein R 2 is C 3-8 -cycloalk(en)yl, typically C 3-6 -cycloalk(en)yl.

在再一个实施方案中，本发明涉及式I化合物，其中R2为芳基。In yet another embodiment, the invention relates to compounds of formula I, wherein R 2 is aryl.

在再一个实施方案中，本发明涉及式I化合物，其中R2为芳基-C1-6-烷(烯/炔)基，通常为芳基-C1-3-烷(烯/炔)基。In yet another embodiment, the invention relates to compounds of formula I, wherein R 2 is aryl-C 1-6 -alk(en/yn)yl, typically aryl-C 1-3 -alk(en/yn) base.

在再一个实施方案中，本发明涉及式I化合物，其中R2为卤代-C1-6-烷(烯/炔)基，通常为卤代-C1-3-烷(烯/炔)基。In yet another embodiment, the present invention relates to compounds of formula I, wherein R 2 is halo-C 1-6 -alk(en/yn)yl, typically halo-C 1-3 -alk(en/yne) base.

在再一个实施方案中，本发明涉及式I化合物，其中s为0且R2为卤原子。In yet another embodiment, the invention relates to compounds of formula I, wherein s is 0 and R 2 is a halogen atom.

在再一个实施方案中，本发明涉及式I化合物，其中s为0且R2为氰基。In yet another embodiment, the invention relates to compounds of formula I, wherein s is 0 and R is cyano.

在另一个优选实施方案中，本发明涉及式I化合物，其中s为0且R2为NO2。In another preferred embodiment, the invention relates to compounds of formula I, wherein s is 0 and R2 is NO2 .

在一个优选实施方案中，本发明涉及式I化合物，其中R2为氢原子；条件是当s为1时，U为NR11、O或S。In a preferred embodiment, the invention relates to compounds of formula I, wherein R 2 is a hydrogen atom; with the proviso that when s is 1, U is NR 11 , O or S.

在一个实施方案中，本发明涉及式I化合物，其中R2为氢原子；条件是当s为1时，U为NR11。In one embodiment, the invention relates to compounds of formula I, wherein R 2 is a hydrogen atom; with the proviso that when s is 1, U is NR 11 .

在另一个实施方案中，本发明涉及式I化合物，其中R2为氢原子，s为1，U为NR11且R11为氢原子。In another embodiment, the invention relates to compounds of formula I, wherein R 2 is a hydrogen atom, s is 1, U is NR 11 and R 11 is a hydrogen atom.

在一个实施方案中，本发明涉及式I化合物，其中基团-(U)sR2连接在吲哚或二氢吲哚的6位。In one embodiment, the invention relates to compounds of formula I, wherein the group -(U) s R 2 is attached at the 6-position of the indole or indoline.

在一个优选实施方案中，本发明涉及式I化合物，其中基团-(U)sR2连接在吲哚或二氢吲哚的4位。In a preferred embodiment, the invention relates to compounds of formula I, wherein the group -(U) s R 2 is attached to the 4-position of indole or indoline.

在一个优选实施方案中，本发明涉及式I化合物，其中X为CO。In a preferred embodiment, the invention relates to compounds of formula I, wherein X is CO.

在一个优选实施方案中，本发明涉及式I化合物，其中X为SO2。In a preferred embodiment, the invention relates to compounds of formula I, wherein X is SO2 .

在一个优选实施方案中，本发明涉及式I化合物，其中q为0。In a preferred embodiment, the invention relates to compounds of formula I, wherein q is 0.

在一个优选实施方案中，本发明涉及式I化合物，其中q为1。In a preferred embodiment, the invention relates to compounds of formula I, wherein q is 1 .

在一个实施方案中，本发明涉及式I化合物，其中q为1且Z为硫原子。In one embodiment, the invention relates to compounds of formula I, wherein q is 1 and Z is a sulfur atom.

在一个优选实施方案中，本发明涉及式I化合物，其中q为1且Z为氧原子。In a preferred embodiment, the invention relates to compounds of formula I, wherein q is 1 and Z is an oxygen atom.

在一个实施方案中，本发明涉及式I化合物，其中X为SO2且q为0。In one embodiment, the invention relates to compounds of formula I, wherein X is SO 2 and q is 0.

在一个实施方案中，本发明涉及式I化合物，其中X为CO且q为0。In one embodiment, the invention relates to compounds of formula I, wherein X is CO and q is 0.

在一个实施方案中，本发明涉及式I化合物，其中X为CO，q为1且Z为氧原子。In one embodiment, the invention relates to compounds of formula I, wherein X is CO, q is 1 and Z is an oxygen atom.

在一个实施方案中，本发明涉及式I化合物，其中R3选自C1-6-烷(烯/炔)基-杂环烷(烯)基、芳基-杂环烷(烯)基、芳基-C1-6-烷(烯/炔)基-杂环烷(烯)基、C1-6-烷(烯/炔)基氧基-杂环烷(烯)基、C1-6-烷(烯/炔)基氧基-羰基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基氧基-羰基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基氧基-羰基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-杂环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、羟基-C1-6-烷(烯/炔)基-杂环烷(烯)基、卤代-杂环烷(烯)基、卤代-C1-6-烷(烯/炔)基-杂环烷(烯)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-杂环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、氰基-C1-6-烷(烯/炔)基-杂环烷(烯)基、酰基-C1-6-烷(烯/炔)基、酰基-C3-8-环烷(烯)基、酰基-杂环烷(烯)基、酰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、酰基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基和酰基-C1-6-烷(烯/炔)基-杂环烷(烯)基。In one embodiment, the invention relates to compounds of formula I, wherein R is selected from C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, aryl-heterocycloalk(en)yl, Aryl-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, C 1-6 -alk(en/yn)yloxy-heterocycloalk(en)yl, C 1- 6 -alk(en/yn)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yloxy-carbonyl-C 1-6 -alk( En/alkynyl) group, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, hydroxyl- C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C 3-8 -cycloalk(en)yl -C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, hydroxy-C 1-6 -alk( En/alkyn)yl-heterocycloalkan(en)yl, halo-heterocycloalk(en)yl, halo-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, cyano -C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C 3-8 -cyclo Alk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, cyano- C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, acyl-C 1-6 -alk(en/yn)yl, acyl-C 3-8 -cycloalk(en)yl, Acyl-heterocycloalkan(en)yl, Acyl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Acyl-C 1-6 -alk(en/yne) -C 3-8 -cycloalk(en)yl and acyl-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl.

在另一个实施方案中，本发明涉及式I化合物，其中R3选自C1- 6-烷(烯/炔)基、C3-8-环烷(烯)基、杂环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基氧基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基氧基-C3-8-环烷(烯)基、芳基-氧基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、卤代-C1-6-烷(烯/炔)基-芳基、卤代-C3-8-环烷(烯)基-芳基、卤代-C3-8-环烷(烯)基-C1-6烷(烯/炔)基-芳基、卤代-C1-6-烷(烯/炔)基-C3- 8-环烷(烯)基-芳基和-NR12R12’；条件是当R3为NR12R12’时，q为0。In another embodiment, the present invention relates to compounds of formula I, wherein R 3 is selected from C 1- 6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, heterocycloalk(en) C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en) Base, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-C 3-8 -cycloalk(en)yl -C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, C 1-6 -alk(en)yl /Alkynyloxy-C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yloxy-C 1-6 -alk(en/yn)yl, C 1- 6 -alk(en/yn)yloxy-C 3-8 -cycloalk(en)yl, aryl-oxy-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalkane (en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, halo-C 1-6 -alk(en/yn)yl-aryl, halo-C 3-8 -cycloalk(en)yl-aryl, halo -C 3-8 -cycloalk(en)yl-C 1-6alk (en/yn)yl-aryl, halo-C 1-6 -alk(en/yn)yl-C 3- 8 -ring Alk(en)yl-aryl and -NR12R12 ' ; with the proviso that when R3 is NR12R12 ' , q is 0.

在再一个实施方案中，本发明涉及式I化合物，其中R3选自C1- 6-烷(烯/炔)基、C3-8-环烷(烯)基、杂环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基-氧基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基和-NR12R12’；条件是当R3为NR12R12’时，q为0。In yet another embodiment, the present invention relates to compounds of formula I, wherein R 3 is selected from C 1- 6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, heterocycloalk(en) C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en) Base, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-C 3-8 -cycloalk(en)yl -C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, aryl-oxyl-C 1 -6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, halo-C 1-6- Alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 alk(en/yn)yl, Halo-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl and -NR 12 R 12' ; with the proviso that when R 3 is NR 12 R 12' , q is 0.

在再一个实施方案中，本发明涉及式I化合物，其中R3选自C1- 6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、C1- 6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基-氧基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基和-NR12R12’；条件是当R3为NR12R12’时，q为0。In yet another embodiment, the present invention relates to compounds of formula I, wherein R 3 is selected from C 1- 6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cyclo Alk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, aryl, aryl- C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk( En/alkyn)yl, aryl-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, aryl-oxy-C 1-6 -alk(en/alkyne) ) base, aryl-C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)-yl and -NR 12 R 12' ; provided that when R 3 is NR 12 R 12' , q is 0.

在一个优选实施方案中，本发明涉及式I化合物，其中R3选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、杂环烷(烯)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-氧基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基和-NR12R12’；条件是当R3为NR12’R12’时，q为0。In a preferred embodiment, the present invention relates to compounds of formula I, wherein R 3 is selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, heterocycloalk(en)yl base, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-oxy-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk( En/alkynyloxy-C 1-6 -alk(en/alkyn)yl, halo-C 1-6 -alk(en/alkyn)yl and -NR 12 R 12' ; with the proviso that when R 3 is When NR 12' R 12' , q is 0.

在另一个优选实施方案中，本发明涉及式I化合物，其中R3选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-氧基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基和-NR12R12’；条件是当R3为NR12R12’时，q为0。In another preferred embodiment, the present invention relates to compounds of formula I, wherein R 3 is selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, aryl, aryl -C 1-6 -alk(en/yn)yl, aryl-oxy-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yloxy -C 1-6 -alk(en/yn)yl and -NR 12 R 12' ; with the proviso that when R 3 is NR 12 R 12' , q is 0.

在另一个优选实施方案中，本发明涉及式I化合物，其中R3为C1-6-烷(烯/炔)基，通常为C1-3-烷(烯/炔)基。In another preferred embodiment, the invention relates to compounds of formula I, wherein R 3 is C 1-6 -alk(en/yn)yl, typically C 1-3 -alk(en/yn)yl.

在再一个优选实施方案中，本发明涉及式I化合物，其中R3为C3-8-环烷(烯)基。In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R 3 is C 3-8 -cycloalk(en)yl.

在再一个优选实施方案中，本发明涉及式I化合物，其中R3为C3-8-环烷(烯)基-C1-6-烷(烯/炔)基。In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R 3 is C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl.

在再一个优选实施方案中，本发明涉及式I化合物，其中R3为杂环烷(烯)基。In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R 3 is heterocycloalk(en)yl.

在再一个优选实施方案中，本发明涉及式I化合物，其中R3为芳基。In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R 3 is aryl.

在再一个优选实施方案中，本发明涉及式I化合物，其中R3为芳基-C1-6-烷(烯/炔)基。In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R 3 is aryl-C 1-6 -alk(en/yn)yl.

在再一个优选实施方案中，本发明涉及式I化合物，其中R3为C1-6-烷(烯/炔)基-氧基-C1-6-烷(烯/炔)基。In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R 3 is C 1-6 -alk(en/yn)yl-oxy-C 1-6 -alk(en/yn)yl.

在再一个优选实施方案中，本发明涉及式I化合物，其中R3为芳基-氧基-C1-6-烷(烯/炔)基。In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R 3 is aryl-oxy-C 1-6 -alk(en/yn)yl.

在再一个优选实施方案中，本发明涉及式I化合物，其中R3为芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基。In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R 3 is aryl-C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl.

在再一个实施方案中，本发明涉及式I化合物，其中R3为C1-6-烷(烯/炔)基氧基-羰基-C1-6-烷(烯/炔)基。In yet another embodiment, the invention relates to compounds of formula I, wherein R 3 is C 1-6 -alk(en/yn)yloxy-carbonyl-C 1-6 -alk(en/yn)yl.

在再一个实施方案中，本发明涉及式I化合物，其中R3为卤代-C1-6-烷(烯/炔)基，如卤代-C1-3-烷(烯/炔)基。In yet another embodiment, the present invention relates to compounds of formula I, wherein R 3 is halo-C 1-6 -alk(en/yn)yl, such as halo-C 1-3 -alk(en/yn)yl .

在再一个实施方案中，本发明涉及式I化合物，其中R3为卤代-C1-6-烷(烯/炔)基-芳基，如卤代-C1-3-烷(烯/炔)基-芳基。In yet another embodiment, the present invention relates to compounds of formula I, wherein R 3 is halo-C 1-6 -alk(en/yn)yl-aryl, such as halo-C 1-3 -alk(en/yn) Alkynyl-aryl.

在再一个优选实施方案中，本发明涉及式I化合物，其中R3为-NR12R12’且q为0。In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R 3 is —NR 12 R 12′ and q is 0.

在一个实施方案中，本发明涉及式I化合物，其中X为CO，q为1，Z为氧原子，R3选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基-氧基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基和卤代-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基。In one embodiment, the invention relates to compounds of formula I, wherein X is CO, q is 1, Z is an oxygen atom, R 3 is selected from C 1-6 -alk(en/yn)yl, C 3-8 -ring Alk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl-C 3-8 -cyclo Alk(en)yl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-C 3-8 -cycloalk(en)yl Base-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, aryl-oxy-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yne) and halo-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl.

在另一个实施方案中，本发明涉及式I化合物，其中X为CO，q为1，Z为氧原子，R3选自C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基和卤代-C1-6-烷(烯/炔)基。In another embodiment, the present invention relates to compounds of formula I, wherein X is CO, q is 1, Z is an oxygen atom, R 3 is selected from C 1-6 -alk(en/yn)yl, aryl-C 1 -6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl and halo-C 1-6 -alk(en/yn)yl.

在另一个实施方案中，本发明涉及式I化合物，其中X为CO，q为0，R3选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、杂环烷(烯)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基-氧基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基和-NR12R12’。In another embodiment, the present invention relates to compounds of formula I, wherein X is CO, q is 0, R 3 is selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en) C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en) group, heterocycloalk(en)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, Aryl-oxy-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl and -NR 12 R 12' .

在再一个实施方案中，本发明涉及式I化合物，其中X为CO，q为0，R3选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、杂环烷(烯)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-氧基-C1-6-烷(烯/炔)基和-NR12R12’。In yet another embodiment, the present invention relates to compounds of formula I, wherein X is CO, q is 0, R 3 is selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en) group, heterocycloalk(en)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-oxy-C 1-6 -alk(en/yn)yl and -NR 12 R 12' .

在再一个实施方案中，本发明涉及式I化合物，其中X为SO2，q为0，R3选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基和芳基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基。In yet another embodiment, the present invention relates to compounds of formula I, wherein X is SO 2 , q is 0, R 3 is selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en) ) group, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en) ) group, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-C 3-8 -cycloalk(en)yl-C 1-6 -Alk(en/yn)yl and aryl-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl.

在再一个实施方案中，本发明涉及式I化合物，其中X为SO2，q为0，R3为C1-6-烷(烯/炔)基或芳基-C1-6-烷(烯/炔)基。In yet another embodiment, the present invention relates to compounds of formula I, wherein X is SO 2 , q is 0, R 3 is C 1-6 -alk(en/yn)yl or aryl-C 1-6 -alk( alkenyl/alkynyl).

在一个实施方案中，本发明涉及式I化合物，其中R3为NR12R12’且q为0，其中R12和R12’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基和芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基。In one embodiment, the invention relates to compounds of formula I, wherein R 3 is NR 12 R 12′ and q is 0, wherein R 12 and R 12′ are independently selected from hydrogen, C 1-6 -alk(ene/yne ) group, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl and aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yne) base.

在另一个实施方案中，本发明涉及式I化合物，其中R3为NR12R12’且q为0，其中R12和R12’独立地选自氢、C1-6-烷(烯/炔)基、芳基和芳基-C1-6-烷(烯/炔)基或其中R12和R12’与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子。In another embodiment, the present invention relates to compounds of formula I, wherein R 3 is NR 12 R 12′ and q is 0, wherein R 12 and R 12′ are independently selected from hydrogen, C 1-6 -alk(ene/ Alkynyl) group, aryl group and aryl-C 1-6 -alk(en/alkyn) group or wherein R 12 and R 12' together with the nitrogen atom to which they are attached form a 4 to 8 membered saturated or unsaturated ring, said ring Optionally 1, 2 or 3 further heteroatoms are included.

在一个优选实施方案中，本发明涉及式I化合物，其中R3为NR12R12’且q为0，其中R12和R12’独立地选自氢、C1-6-烷(烯/炔)基、芳基和芳基-C1-6-烷(烯/炔)基。In a preferred embodiment, the present invention relates to compounds of formula I, wherein R 3 is NR 12 R 12′ and q is 0, wherein R 12 and R 12′ are independently selected from hydrogen, C 1-6 -alk(ene/ Alkynyl, aryl and aryl-C 1-6 -alk(en/yn)yl.

在另一个优选实施方案中，本发明涉及式I化合物，其中R3为NR12R12’且q为0，其中R12和R12与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子。In another preferred embodiment, the invention relates to compounds of formula I, wherein R 3 is NR 12 R 12′ and q is 0, wherein R 12 and R 12 together with the nitrogen atom to which they are attached form a 4 to 8 membered saturated or unsaturated ring, which ring optionally contains 1, 2 or 3 other heteroatoms.

在一个实施方案中，本发明涉及式I化合物，其中R3为NR12R12’且q为0，其中R12和R12’中至少一个为氢原子。In one embodiment, the invention relates to compounds of formula I, wherein R 3 is NR 12 R 12′ and q is 0, wherein at least one of R 12 and R 12′ is a hydrogen atom.

在另一个实施方案中，本发明涉及式I化合物，其中R3为NR12R12’且q为0，其中R12和R12’中至少一个为C1-6-烷(烯/炔)基，通常为C1-3-烷(烯/炔)基。In another embodiment, the invention relates to compounds of formula I, wherein R 3 is NR 12 R 12' and q is 0, wherein at least one of R 12 and R 12' is C 1-6 -alk(ene/yne) A group, typically a C 1-3 -alk(en/yn)yl group.

在再一个实施方案中，本发明涉及式I化合物，其中R3为NR12R12’且q为0，其中R12和R12’中的一个为芳基。In yet another embodiment, the invention relates to compounds of formula I, wherein R 3 is NR 12 R 12′ and q is 0, wherein one of R 12 and R 12′ is aryl.

在再一个实施方案中，本发明涉及式I化合物，其中R3为NR12R12’且q为0，R12和R12’中的一个为芳基-C1-6-烷(烯/炔)基，通常为芳基-C1-3-烷(烯/炔)基。In yet another embodiment, the invention relates to compounds of formula I, wherein R 3 is NR 12 R 12' and q is 0, one of R 12 and R 12' is aryl-C 1-6 -alk(ene/ Alkynyl) group, typically aryl-C 1-3 -alk(en/yn)yl.

在一个优选实施方案中，本发明涉及式I化合物，其中Y为式II、III、V、XXX或XXXI。In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula II, III, V, XXX or XXXI.

在一个实施方案中，本发明涉及式I化合物，其中Y为式III或IV。In one embodiment, the invention relates to compounds of formula I, wherein Y is formula III or IV.

在一个优选实施方案中，本发明涉及式I化合物，其中Y为式II或V。In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula II or V.

在一个优选实施方案中，本发明涉及式I化合物，其中Y为式V或XXXI。In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is formula V or XXXI.

在一个优选实施方案中，本发明涉及式I化合物，其中Y为式II或III且W为硫原子。In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula II or III and W is a sulfur atom.

在一个优选实施方案中，本发明涉及式I化合物，其中Y为式II或III且W为氧原子。In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula II or III and W is an oxygen atom.

在一个优选实施方案中，本发明涉及式I化合物，其中Y为式V。In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula V.

在一个优选实施方案中，本发明涉及式I化合物，其中Y为式XXX且T为NH。In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula XXX and T is NH.

在一个优选实施方案中，本发明涉及式I化合物，其中Y为式XXX且T为氮原子或氧原子。In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula XXX and T is a nitrogen atom or an oxygen atom.

在一个优选实施方案中，本发明涉及式I化合物，其中Y为式XXXI且L为氮原子。In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula XXXI and L is a nitrogen atom.

在一个优选实施方案中，本发明涉及式I化合物，其中Y为式XXXI且L为C或CH。In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula XXXI and L is C or CH.

在一个实施方案中，本发明涉及式I化合物，其中R5各自独立地选自芳基-C1-6-烷(烯/炔)基、酰基、-CO-NR6NR6’、氰基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基。In one embodiment, the present invention relates to compounds of formula I, wherein each R 5 is independently selected from aryl-C 1-6 -alk(en/yn)yl, acyl, -CO-NR 6 NR 6' , cyano , cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1- 6 -Alk(en/yn)yl.

在另一个实施方案中，本发明涉及式I化合物，其中R5各自独立地选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、C1-6-烷(烯/炔)基氧基、C3-8-环烷(烯)基氧基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基氧基、卤素、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、-NR7R7’、-S-R8和-SO2R8；或两个相邻的R5与其连接的芳基一起形成任选包含一个或两个杂原子的4至8元环。In another embodiment, the present invention relates to compounds of formula I, wherein each R 5 is independently selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en) yloxy, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy, halogen, halo-C 1-6 -alk(en/yn)yl, halo Substituted-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, -NR 7 R 7' ,- SR 8 and —SO 2 R 8 ; or two adjacent R 5 together with the aryl to which they are attached form a 4 to 8 membered ring optionally containing one or two heteroatoms.

在再一个实施方案中，本发明涉及式I化合物，其中R5各自独立地选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、C1-6-烷(烯/炔)基氧基、C3-8-环烷(烯)基氧基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基氧基、-NR7R7’、-S-R8和-SO2R8；或两个相邻的R5与其连接的芳基一起形成任选包含一个或两个杂原子的4至8元环。In yet another embodiment, the present invention relates to compounds of formula I, wherein each R 5 is independently selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en) yloxy, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy, -NR 7 R 7' , -SR 8 and -SO 2 R 8 ; or both Each adjacent R5 together with the aryl to which it is attached forms a 4 to 8 membered ring optionally containing one or two heteroatoms.

在再一个实施方案中，本发明涉及式I化合物，其中R5各自独立地选自卤素、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基和卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基。In yet another embodiment, the present invention relates to compounds of formula I, wherein each R 5 is independently selected from halogen, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalkane (en)yl and halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl.

在再一个实施方案中，本发明涉及式I化合物，其中R5各自独立地选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-硫基、芳基-氧基、卤原子、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基或两个相邻的R5与其连接的芳基一起形成任选包含一个或两个杂原子的4至8元环。In yet another embodiment, the present invention relates to compounds of formula I, wherein each R 5 is independently selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl, aryl-sulfanyl, aryl-oxyl, halogen atom, halo-C 1-6 -alk( En/alkynyl) group, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl or two Each adjacent R5 together with the aryl to which it is attached forms a 4 to 8 membered ring optionally containing one or two heteroatoms.

在一个优选实施方案中，本发明涉及式I化合物，其中R5各自独立地选自C1-6-烷(烯/炔)基、芳基、芳基-硫基、芳基-氧基、卤素、卤代-C1-6-烷(烯/炔)基或两个相邻的R5与其连接的芳基一起形成任选包含一个或两个杂原子的4至8元环。In a preferred embodiment, the present invention relates to compounds of formula I, wherein R 5 are each independently selected from C 1-6 -alk(en/yn)yl, aryl, aryl-thio, aryl-oxy, Halogen, halo-C 1-6 -alk(en/yn)yl or two adjacent R 5 together with the aryl to which it is attached form a 4 to 8 membered ring optionally containing one or two heteroatoms.

在另一个优选实施方案中，本发明涉及式I化合物，其中R5各自独立地选自卤素和卤代-C1-6-烷(烯/炔)基。In another preferred embodiment, the present invention relates to compounds of formula I, wherein each R 5 is independently selected from halogen and halo-C 1-6 -alk(en/yn)yl.

在一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为卤原子。In one embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is a halogen atom.

在另一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为卤代-C1-6-烷(烯/炔)基，通常为卤代-C1-3-烷(烯/炔)基。In another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is halo-C 1-6 -alk(en/yn)yl, typically halo-C 1-3 -alk( alkenyl/alkynyl).

在再一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为C1-6-烷(烯/炔)基。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is C 1-6 -alk(en/yn)yl.

在再一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为芳基。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is aryl.

在再一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为芳基-硫基。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is aryl-thio.

在再一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为芳基-氧基。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is aryl-oxy.

在再一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为C1-6-烷(烯/炔)基氧基。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is C 1-6 -alk(en/yn)yloxy.

在再一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为-NR7R7’。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is —NR 7 R 7′ .

在再一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为-S-R8。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is —SR 8 .

在再一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为-SO2R8。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is —SO 2 R 8 .

在再一个实施方案中，本发明涉及式I化合物，其中两个相邻的R5与其连接的芳基一起形成任选包含一个或两个杂原子的4至8元环。In yet another embodiment, the invention relates to compounds of formula I, wherein two adjacent R 5 together with the aryl to which they are attached form a 4 to 8 membered ring optionally comprising one or two heteroatoms.

在一个优选实施方案中，本发明涉及式I化合物，其中两个相邻的R5一起形成-(CH2)n’-CH2-、-CH＝CH-(CH2)m’-、-CH2-CH＝CH-(CH2)p’-、-CH＝CH-CH＝CH-、-(CH2)n’-O-、-O-(CH2)m’-O-、-CH2-O-(CH2)p’-O-、-CH2-O-CH2-O-CH2-、-(CH2)n’-S-、-S-(CH2)m’-S-、-CH2-S-(CH2)p’-S-、-CH2-S-CH2-S-CH2-、-(CH2)n’-NH-、-NH-(CH2)m’-NH-、-CH2-NH-(CH2)p’-NH-、-CH＝CH-NH-、-O-(CH2)m’-NH-、-CH2-O-(CH2)p’-NH-或-O-(CH2)p’-NH-CH2-、-S-(CH2)m’-NH-、-N＝CH-NH-、-N＝CH-O-或-N＝CH-S-，其中m’为1、2或3，n’为2、3或4且p’为1或2。In a preferred embodiment, the invention relates to compounds of formula I, wherein two adjacent R 5 together form -(CH 2 ) n' -CH 2 -, -CH═CH-(CH 2 ) m' -, - CH 2 -CH=CH-(CH 2 ) p' -, -CH=CH-CH=CH-, -(CH 2 ) n' -O-, -O-(CH 2 ) m' -O-, - CH 2 -O-(CH 2 ) p' -O-, -CH 2 -O-CH 2 -O-CH 2 -, -(CH 2 ) n' -S-, -S-(CH 2 ) m' -S-, -CH 2 -S-(CH 2 ) p' -S-, -CH 2 -S-CH 2 -S-CH 2 -, -(CH 2 ) n' -NH-, -NH-( CH 2 ) m' -NH-, -CH 2 -NH-(CH 2 ) p' -NH-, -CH=CH-NH-, -O-(CH 2 ) m' -NH-, -CH 2 - O-(CH 2 ) p' -NH- or -O-(CH 2 ) p' -NH-CH 2 -, -S-(CH 2 ) m' -NH-, -N=CH-NH-, - N=CH-O- or -N=CH-S-, wherein m' is 1, 2 or 3, n' is 2, 3 or 4 and p' is 1 or 2.

在再一个实施方案中，本发明涉及式I化合物，其中两个相邻的R5一起形成-CH2-O-CH2-。In yet another embodiment, the invention relates to compounds of formula I, wherein two adjacent R 5 are taken together to form -CH 2 -O-CH 2 -.

在再一个实施方案中，本发明涉及式I化合物，其中两个相邻的R5一起形成-CH＝CH-CH＝CH-。In yet another embodiment, the invention relates to compounds of formula I, wherein two adjacent R 5 are taken together to form -CH=CH-CH=CH-.

在再一个实施方案中，本发明涉及式I化合物，其中两个相邻的R5一起形成-O-CH2-O-。In yet another embodiment, the invention relates to compounds of formula I, wherein two adjacent R 5 are taken together to form -O-CH 2 -O-.

在再一个实施方案中，本发明涉及式I化合物，其中两个相邻的R5一起形成-O-CH2-O-CH2-。In yet another embodiment, the invention relates to compounds of formula I, wherein two adjacent R 5 are taken together to form -O-CH 2 -O-CH 2 -.

在再一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为-NR7R7’；且其中R7和R7’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基和C3-8-环烷(烯)基-C1-6-烷(烯/炔)基。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is -NR 7 R 7' ; and wherein R 7 and R 7' are independently selected from hydrogen, C 1-6 -alk( En/yn)yl, C 3-8 -cycloalk(en)yl and C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl.

在再一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为-NR7R7’；且其中R7和R7’独立地选自氢和C1-6-烷(烯/炔)基。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is -NR 7 R 7' ; and wherein R 7 and R 7' are independently selected from hydrogen and C 1-6 -alk( alkenyl/alkynyl).

在再一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为-NR7R7’；且其中R7和R7’均为C1-6-烷(烯/炔)基，通常为C1-3-烷(烯/炔)基。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is -NR 7 R 7' ; and wherein both R 7 and R 7' are C 1-6 -alk(en/yne) A group, typically a C 1-3 -alk(en/yn)yl group.

在再一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为-S-R8或-SO2R8；且其中R8选自氢、C1-6-烷(烯/炔)基、C3- 8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基和芳基。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is -SR 8 or -SO 2 R 8 ; and wherein R 8 is selected from hydrogen, C 1-6 -alk(en/yne ) group, C 3- 8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl and aryl.

在再一个实施方案中，本发明涉及式I化合物，其中至少一个取代基R5为-S-R8或-SO2R8；且其中R8选自C1-6-烷(烯/炔)基和芳基。In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R 5 is -SR 8 or -SO 2 R 8 ; and wherein R 8 is selected from C 1-6 -alk(en/yn)yl and aryl.

本发明的一个实施方案涉及式I化合物，其中s为0且q为0。One embodiment of the invention relates to compounds of formula I, wherein s is 0 and q is 0.

本发明的另一个实施方案涉及式I化合物，其中R2为氢原子且X为CO。Another embodiment of this invention relates to compounds of formula I, wherein R2 is a hydrogen atom and X is CO.

本发明的再一个实施方案涉及式I化合物，其中s为0且X为CO。A further embodiment of the present invention relates to compounds of formula I, wherein s is 0 and X is CO.

本发明的再一个实施方案涉及式I化合物，其中R2为氢原子且q为0。Yet another embodiment of the present invention relates to compounds of formula I, wherein R 2 is a hydrogen atom and q is 0.

本发明的再一个实施方案涉及式I化合物，其中q为0且X为CO。A further embodiment of the present invention relates to compounds of formula I, wherein q is 0 and X is CO.

本发明的一个实施方案涉及式I化合物，其中在取代基R2、R3和R5中芳基总数等于0、1、2或3，通常为0或1。One embodiment of the invention relates to compounds of formula I, wherein the total number of aryl groups in the substituents R2 , R3 and R5 is equal to 0, 1, 2 or 3, typically 0 or 1.

本发明的另一个实施方案涉及式I化合物，其中R2、R3或R5都不包含芳基。Another embodiment of this invention relates to compounds of formula I, wherein none of R2 , R3 or R5 comprises an aryl group.

本发明的再一个实施方案涉及式I化合物，其中在取代基R2、R3和R5中芳基总数等于1。A further embodiment of the invention relates to compounds of formula I, wherein the total number of aryl groups in the substituents R 2 , R 3 and R 5 is equal to one.

本发明的再一个实施方案涉及式I化合物，其中在取代基R2、R3和R5中芳基总数等于2。Yet another embodiment of the present invention relates to compounds of formula I, wherein the total number of aryl groups in the substituents R 2 , R 3 and R 5 is equal to two.

本发明的一个实施方案涉及式I化合物，其中当X为SO2且q为0时，R3不为CH3。One embodiment of the invention relates to compounds of formula I, wherein when X is SO2 and q is 0, R3 is other than CH3 .

本发明的另一个实施方案涉及式I化合物，其中当Y为式V时，X-(Z)q-R3均不为SO2-CH3。Another embodiment of the present invention relates to compounds of formula I, wherein when Y is formula V, none of X-(Z) q -R 3 is SO 2 -CH 3 .

本发明的再一个实施方案涉及式I化合物，其中R3为NR12R12’且R12和R12’不为芳基。A further embodiment of the present invention relates to compounds of formula I, wherein R 3 is NR 12 R 12′ and R 12 and R 12′ are not aryl.

本发明的再一个实施方案涉及式I化合物，其中R3为NR12R12’且R12和R12’中的一个为芳基，条件是所述芳基不为喹啉或苯基。Yet another embodiment of the present invention relates to compounds of formula I, wherein R 3 is NR 12 R 12′ and one of R 12 and R 12′ is aryl, with the proviso that said aryl is not quinoline or phenyl.

本发明的另一个实施方案涉及式I化合物，其中当X为CO，q为0且R3为NR12R12’，且R12和R12’中的一个为芳基，所述芳基通常为喹啉或苯基时，Y不为式V。Another embodiment of the present invention relates to compounds of formula I, wherein when X is CO, q is 0 and R 3 is NR 12 R 12' , and one of R 12 and R 12' is aryl, said aryl is usually When it is quinoline or phenyl, Y is not formula V.

在另一个实施方案中，式I化合物不为：In another embodiment, the compound of formula I is not:

N-[1-(苯基甲基)-1H吲哚-5-基]-甲磺酰胺；N-[1-(phenylmethyl)-1H indol-5-yl]-methanesulfonamide;

N-[1-[(4-氟苯基)甲基]-1H吲哚-5-基]-甲磺酰胺；N-[1-[(4-fluorophenyl)methyl]-1H indol-5-yl]-methanesulfonamide;

N-[2，3-二氢-1-(苯基甲基)-1H-吲哚-5-基]-甲磺酰胺；N-[2,3-dihydro-1-(phenylmethyl)-1H-indol-5-yl]-methanesulfonamide;

N-[1-(苯基甲基)-1H-吲哚-5-基]-N’-4-喹啉基-脲；N-[1-(phenylmethyl)-1H-indol-5-yl]-N'-4-quinolyl-urea;

N-[1-(苯基甲基)-1H吲哚-5-基]-N’-4-喹啉基-脲；或N-[1-(phenylmethyl)-1Hindol-5-yl]-N'-4-quinolyl-urea; or

1-(1-苄基-5-二氢吲哚基)-3-苯基-脲。1-(1-Benzyl-5-dihydroindolyl)-3-phenyl-urea.

本发明的一方面涉及通式VII的化合物及其盐：One aspect of the present invention relates to compounds of general formula VII and salts thereof:

Figure A20048001101900491
Figure A20048001101900491

其中虚线、f、q、s、U、X、Z、R1、R1’、R2、R3和R5如式I定义。涉及式I的任何实施方案也为式VII的实施方案。Wherein the dotted line, f, q, s, U, X, Z, R 1 , R 1′ , R 2 , R 3 and R 5 are as defined in formula I. Any embodiment involving formula I is also an embodiment of formula VII.

在一个实施方案中，本发明涉及通式VII的化合物，其中f为0。In one embodiment, the invention relates to compounds of general formula VII, wherein f is zero.

在另一个实施方案中，本发明涉及通式VII的化合物，所述化合物被一个取代基R5取代(如在邻、间或对位)。In another embodiment, the invention relates to compounds of general formula VII substituted by one substituent R 5 (eg in the ortho, meta or para position).

在一个优选实施方案中，本发明涉及对位被一个取代基R5取代的通式VII的化合物。In a preferred embodiment, the invention relates to compounds of general formula VII substituted in the para position by one substituent R 5 .

在一个实施方案中，本发明涉及通式VII的化合物，所述化合物被两个独立选择的R5取代基取代(如在邻和对位、间和对位以及邻和间位)。In one embodiment, the invention relates to compounds of general formula VII substituted with two independently selected R substituents (eg at ortho and para, meta and para and ortho and meta).

在另一个实施方案中，本发明涉及被三个独立选择的R5取代基取代的通式VII的化合物。In another embodiment, the invention relates to compounds of general formula VII substituted with three independently selected R substituents.

本发明的另一方面涉及通式VIII的化合物或其盐：Another aspect of the present invention relates to compounds of general formula VIII or salts thereof:

Figure A20048001101900501
Figure A20048001101900501

其中虚线、g、h、q、s、U、X、Z、R1、R1’、R2、R3和R5如式I定义。涉及式I的任何实施方案也为式VIII的实施方案。Wherein the dotted line, g, h, q, s, U, X, Z, R 1 , R 1' , R 2 , R 3 and R 5 are as defined in formula I. Any embodiment involving formula I is also an embodiment of formula VIII.

在一个实施方案中，本发明涉及通式VIII的化合物，其中氮原子通过亚甲基连接在萘基的1位。In one embodiment, the invention relates to compounds of general formula VIII, wherein the nitrogen atom is attached to the 1-position of the naphthyl group via a methylene group.

在另一个实施方案中，本发明涉及通式VIII的化合物，其中氮原子通过亚甲基连接在萘基的2位。In another embodiment, the invention relates to compounds of general formula VIII, wherein the nitrogen atom is attached to the 2-position of naphthyl through a methylene group.

在再一个实施方案中，本发明涉及通式VIII的化合物，其中g为0、1、2或3，通常为0、1或2。In yet another embodiment, the invention relates to compounds of general formula VIII, wherein g is 0, 1, 2 or 3, typically 0, 1 or 2.

在再一个实施方案中，本发明涉及通式VIII的化合物，其中h为0、1或2，通常为0或1。In yet another embodiment, the invention relates to compounds of general formula VIII, wherein h is 0, 1 or 2, typically 0 or 1 .

在再一个实施方案中，本发明涉及通式VIII的化合物，其中g+h等于0、1、2或3。In yet another embodiment, the invention relates to compounds of general formula VIII, wherein g+h is equal to 0, 1, 2 or 3.

在再一个实施方案中，本发明涉及通式的VIII化合物，其中g和h都为0。In yet another embodiment, the invention relates to compounds of formula VIII, wherein g and h are both zero.

在再一个实施方案中，本发明涉及被一个R5取代基取代的通式VIII的化合物。In yet another embodiment, the invention relates to compounds of general formula VIII substituted with one R substituent.

在再一个实施方案中，本发明涉及被两个独立选择的R5取代基取代的通式VIII的化合物。In yet another embodiment, the invention relates to compounds of general formula VIII substituted with two independently selected R substituents.

在再一个实施方案中，本发明涉及被三个独立选择的R5取代基取代的通式VIII的化合物。In yet another embodiment, the invention relates to compounds of general formula VIII substituted with three independently selected R substituents.

本发明的再一个方面涉及通式IX的化合物或其盐：Another aspect of the present invention relates to a compound of general formula IX or a salt thereof:

Figure A20048001101900511
Figure A20048001101900511

其中虚线、a、q、s、U、X、Z、R1、R1’、R2、R3和R5如式I定义。涉及式I的任何实施方案也为式IX的实施方案。Wherein the dotted line, a, q, s, U, X, Z, R 1 , R 1′ , R 2 , R 3 and R 5 are as defined in formula I. Any embodiment involving formula I is also an embodiment of formula IX.

在一个实施方案中，本发明涉及通式IX的化合物，其中氮原子通过亚甲基连接在杂芳基的2位。In one embodiment, the invention relates to compounds of general formula IX, wherein the nitrogen atom is attached to the 2-position of the heteroaryl through a methylene group.

在另一个实施方案中，本发明涉及通式IX的化合物，其中氮原子通过亚甲基连接在杂芳基的3位。In another embodiment, the invention relates to compounds of general formula IX, wherein the nitrogen atom is attached to the 3-position of the heteroaryl through a methylene group.

在再一个实施方案中，本发明涉及通式IX的化合物，其中W为氧原子。In yet another embodiment, the invention relates to compounds of general formula IX, wherein W is an oxygen atom.

在优选实施方案中，本发明涉及通式IX的化合物，其中W为硫原子。In a preferred embodiment, the invention relates to compounds of general formula IX, wherein W is a sulfur atom.

在另一个实施方案中，本发明涉及通式IX的化合物，其中a为0、1或2。In another embodiment, the invention relates to compounds of general formula IX, wherein a is 0, 1 or 2.

在再一个实施方案中，本发明涉及通式IX的化合物，其中a为0。In yet another embodiment, the invention relates to compounds of general formula IX, wherein a is zero.

在再一个实施方案中，本发明涉及被一个取代基R5取代(如在5位)的通式IX的化合物。In yet another embodiment, the invention relates to compounds of general formula IX substituted (eg at position 5 ) by one substituent R5.

在再一个实施方案中，本发明涉及被两个独立选择的R5取代基取代通式IX的化合物。In yet another embodiment, the invention relates to the substitution of a compound of formula IX by two independently selected R substituents.

在一个实施方案中，本发明涉及通式IX的化合物，其中氮原子通过亚甲基连接在杂芳基的2位，其中取代基R5连接在杂芳基的5位。In one embodiment, the invention relates to compounds of general formula IX, wherein the nitrogen atom is attached to the 2-position of the heteroaryl through a methylene group, wherein the substituent R 5 is attached to the 5-position of the heteroaryl.

本发明的再一个方面涉及通式X的化合物或其盐：Yet another aspect of the present invention relates to compounds of general formula X or salts thereof:

其中虚线、b、c、q、s、U、X、Z、R1、R1’、R2、R3和R5如式I定义。涉及式I的任何实施方案也为式X的实施方案。Wherein the dotted line, b, c, q, s, U, X, Z, R 1 , R 1' , R 2 , R 3 and R 5 are as defined in Formula I. Any embodiment involving formula I is also an embodiment of formula X.

在一个实施方案中，本发明涉及通式X的化合物，其中氮原子通过亚甲基连接于杂芳基的2位。In one embodiment, the invention relates to compounds of general formula X, wherein the nitrogen atom is attached to the 2-position of the heteroaryl through a methylene group.

在另一个实施方案中，本发明涉及通式X的化合物，其中氮原子通过亚甲基连接于杂芳基的3位。In another embodiment, the invention relates to compounds of general formula X, wherein the nitrogen atom is attached to the 3-position of the heteroaryl through a methylene group.

在再一个实施方案中，本发明涉及通式X的化合物，其中W为氧原子。In yet another embodiment, the invention relates to compounds of general formula X, wherein W is an oxygen atom.

在再一个实施方案中，本发明涉及通式X的化合物，其中W为硫原子。In yet another embodiment, the invention relates to compounds of general formula X, wherein W is a sulfur atom.

在再一个实施方案中，本发明涉及通式X的化合物，其中b为0、1、2或3，通常为0、1或2。In yet another embodiment, the invention relates to compounds of general formula X, wherein b is 0, 1, 2 or 3, typically 0, 1 or 2.

在再一个实施方案中，本发明涉及通式X的化合物，其中c为0或1，通常为0。In yet another embodiment, the invention relates to compounds of general formula X, wherein c is 0 or 1, usually 0.

在再一个实施方案中，本发明涉及通式X的化合物，其中b+c等于0、1、2、3或4。In yet another embodiment, the invention relates to compounds of general formula X, wherein b+c is equal to 0, 1, 2, 3 or 4.

在再一个实施方案中，本发明涉及通式X的化合物，其中b和c均为0。In yet another embodiment, the invention relates to compounds of general formula X, wherein b and c are both zero.

在再一个实施方案中，本发明涉及通式X的化合物，其中b+c等于1。一种情况是b为1而c为0，另一种情况是b为0而c为1。In yet another embodiment, the invention relates to compounds of general formula X, wherein b+c is equal to 1 . One case is when b is 1 and c is 0, and the other case is when b is 0 and c is 1.

在再一个实施方案中，本发明涉及被一个取代基R5取代的通式X的化合物。In yet another embodiment, the invention relates to compounds of general formula X substituted by one substituent R 5 .

在再一个实施方案中，本发明涉及被两个独立选择的R5取代基取代的通式X的化合物。In yet another embodiment, the invention relates to compounds of general formula X substituted with two independently selected R substituents.

在再一个实施方案中，本发明涉及被三个独立选择的R5取代基取代的通式X的化合物。In yet another embodiment, the invention relates to compounds of general formula X substituted with three independently selected R substituents.

本发明的再一个方面涉及通式XI的化合物或其盐：Yet another aspect of the present invention relates to compounds of general formula XI or salts thereof:

Figure A20048001101900541
Figure A20048001101900541

其中虚线、d、e、q、s、U、X、Z、R1、R1’、R2、R3和R5如式I定义。涉及式I的任何实施方案也为式XI的实施方案。Wherein the dotted line, d, e, q, s, U, X, Z, R 1 , R 1' , R 2 , R 3 and R 5 are as defined in formula I. Any embodiment involving formula I is also an embodiment of formula XI.

在一个实施方案中，本发明涉及通式XI的化合物，其中氮原子通过亚甲基连接于杂芳基的4位。In one embodiment, the invention relates to compounds of general formula XI, wherein the nitrogen atom is attached to the 4-position of the heteroaryl through a methylene group.

在另一个实施方案中，本发明涉及通式XI的化合物，其中氮原子通过亚甲基连接于杂芳基的5位。In another embodiment, the invention relates to compounds of general formula XI, wherein the nitrogen atom is attached to the 5-position of the heteroaryl through a methylene group.

在一个实施方案中，本发明涉及通式XI的化合物，其中氮原子通过亚甲基连接于杂芳基的6位。In one embodiment, the invention relates to compounds of general formula XI, wherein the nitrogen atom is attached to the 6-position of the heteroaryl through a methylene group.

在另一个实施方案中，本发明涉及通式XI的化合物，其中氮原子通过亚甲基连接于杂芳基的7位。In another embodiment, the invention relates to compounds of general formula XI, wherein the nitrogen atom is attached to the 7-position of the heteroaryl through a methylene group.

在再一个实施方案中，本发明涉及通式XI的化合物，其中W为氧原子。In yet another embodiment, the invention relates to compounds of general formula XI, wherein W is an oxygen atom.

在再一个实施方案中，本发明涉及通式XI的化合物，其中W为硫原子。In yet another embodiment, the invention relates to compounds of general formula XI, wherein W is a sulfur atom.

在再一个实施方案中，本发明涉及通式XI的化合物，其中d为0、1或2，通常为0或1。In yet another embodiment, the invention relates to compounds of general formula XI, wherein d is 0, 1 or 2, typically 0 or 1 .

在再一个实施方案中，本发明涉及通式XI的化合物，其中e为0、1或2。In yet another embodiment, the invention relates to compounds of general formula XI, wherein e is 0, 1 or 2.

在再一个实施方案中，本发明涉及通式XI的化合物，其中d+e为0、1、2、3或4。In yet another embodiment, the invention relates to compounds of general formula XI, wherein d+e is 0, 1 , 2, 3 or 4.

在再一个实施方案中，本发明涉及通式XI的化合物，其中d和e均为0。In yet another embodiment, the invention relates to compounds of general formula XI, wherein d and e are both zero.

在再一个实施方案中，本发明涉及被一个取代基R5取代的通式XI的化合物。In yet another embodiment, the invention relates to compounds of general formula XI substituted by one substituent R 5 .

在再一个实施方案中，本发明涉及被两个独立选择的R5取代基取代的通式XI的化合物。In yet another embodiment, the invention relates to compounds of general formula XI substituted with two independently selected R substituents.

在再一个实施方案中，本发明涉及被三个独立选择的R5取代基取代的通式XI的化合物。In yet another embodiment, the invention relates to compounds of general formula XI substituted with three independently selected R substituents.

本发明的再一个方面涉及通式XXXII的化合物或其盐：Another aspect of the present invention relates to a compound of general formula XXXII or a salt thereof:

Figure A20048001101900551
Figure A20048001101900551

其中虚线、j、q、s、T、U、X、Z、R1、R1’、R2、R3和R5如式I定义。涉及式I的任何实施方案也为式XXXII的实施方案。Wherein the dotted line, j, q, s, T, U, X, Z, R 1 , R 1' , R 2 , R 3 and R 5 are as defined in formula I. Any embodiment involving formula I is also an embodiment of formula XXXII.

在一个实施方案中，本发明涉及通式XXXII的化合物，其中氮原子通过亚甲基连接于杂芳基所示1位。In one embodiment, the invention relates to compounds of general formula XXXII, wherein the nitrogen atom is attached to position 1 of the heteroaryl group through a methylene group.

在另一个实施方案中，本发明涉及通式XXXII的化合物，其中氮原子通过亚甲基连接于杂芳基所示2位。In another embodiment, the present invention relates to compounds of general formula XXXII, wherein the nitrogen atom is attached to the 2-position of the heteroaryl group through a methylene group.

在另一个实施方案中，本发明涉及通式XXXII的化合物，其中氮原子通过亚甲基连接于杂芳基所示3位。In another embodiment, the present invention relates to compounds of general formula XXXII, wherein the nitrogen atom is attached to the 3-position of the heteroaryl group through a methylene group.

在再一个实施方案中，本发明涉及通式XXXII的化合物，其中T为氧原子。In yet another embodiment, the invention relates to compounds of general formula XXXII, wherein T is an oxygen atom.

在再一个实施方案中，本发明涉及通式XXXII的化合物，其中T为氮原子。In yet another embodiment, the invention relates to compounds of general formula XXXII, wherein T is a nitrogen atom.

在再一个实施方案中，本发明涉及通式XXXII的化合物，其中T表示NH。In yet another embodiment, the invention relates to compounds of general formula XXXII, wherein T represents NH.

在另一个实施方案中，本发明涉及通式XXXII的化合物，其中j为0、1、2或3。In another embodiment, the invention relates to compounds of general formula XXXII, wherein j is 0, 1, 2 or 3.

在再一个实施方案中，本发明涉及通式XXXII的化合物，其中j为0。In yet another embodiment, the invention relates to compounds of general formula XXXII, wherein j is zero.

在再一个实施方案中，本发明涉及被至少一个取代基R5取代的通式XXXII的化合物。在其一个方面中，通式XXXII的化合物在所示1位上被取代。在其另一方面中，通式XXXII的化合物在所示2位上被取代。在其再一个方面中，通式XXXII的化合物在所示3位上被取代。在其再一个方面中，T表示氮原子，通式XXXII的化合物在该位上被取代。In yet another embodiment, the invention relates to compounds of general formula XXXII substituted by at least one substituent R 5 . In one aspect thereof, compounds of general formula XXXII are substituted at the 1 position shown. In another aspect thereof, the compound of general formula XXXII is substituted at the 2 position shown. In yet another aspect thereof, the compound of formula XXXII is substituted at position 3 as indicated. In yet another aspect thereof, T represents a nitrogen atom at which the compound of general formula XXXII is substituted.

在再一个实施方案中，本发明涉及被两个独立选择的R5取代基取代的通式XXXII的化合物。In yet another embodiment, the invention relates to compounds of general formula XXXII substituted with two independently selected R substituents.

在再一个实施方案中，本发明涉及被两个或三个独立选择的R5取代基取代的通式XXXII的化合物。In yet another embodiment, the invention relates to compounds of general formula XXXII substituted with two or three independently selected R substituents.

在再一个实施方案中，本发明涉及被三个独立选择的R5取代基取代的通式XXXII的化合物。In yet another embodiment, the invention relates to compounds of general formula XXXII substituted with three independently selected R substituents.

本发明的一个方面涉及通式XXXIII的化合物及其盐：One aspect of the present invention relates to compounds of general formula XXXIII and salts thereof:

Figure A20048001101900571
Figure A20048001101900571

其中虚线、k、q、s、L、U、X、Z、R1、R1’、R2、R3和R5如式I定义。涉及式I的任何实施方案也为式XXXIII的实施方案。Wherein the dotted line, k, q, s, L, U, X, Z, R 1 , R 1' , R 2 , R 3 and R 5 are as defined in formula I. Any embodiment involving formula I is also an embodiment of formula XXXIII.

在一个实施方案中，本发明涉及通式XXXIII的化合物，其中k为0。In one embodiment, the invention relates to compounds of general formula XXXIII, wherein k is zero.

在另一个实施方案中，本发明涉及被一个取代基R5取代(如在氮原子的邻、间或对位)的通式XXXIII的化合物。In another embodiment, the invention relates to compounds of general formula XXXIII substituted by one substituent R 5 , eg in the ortho, meta or para position to the nitrogen atom.

在一个优选实施方案中，本发明涉及氮原子的对位被一个取代基R5取代的通式XXXIII的化合物。In a preferred embodiment, the invention relates to compounds of the general formula XXXIII in which the para position of the nitrogen atom is substituted by a substituent R 5 .

在一个实施方案中，本发明涉及被两个独立选择的R5取代基取代(如在氮原子邻和对位，或在氮原子间和对位，或在氮原子邻和间位)的通式XXXIII的化合物。In one embodiment, the present invention is directed to a general compound substituent substituted by two independently selected R substituents (such as at the nitrogen atom ortho and para positions, or at the nitrogen atom and para positions, or at the nitrogen atom ortho and meta positions). A compound of formula XXXIII.

在另一个实施方案中，本发明涉及被三个独立选择的R5取代基取代的通式XXXIII的化合物。In another embodiment, the present invention is concerned with compounds of general formula XXXIII substituted with three independently selected R substituents.

在本发明的一个实施方案中，优选下列化合物和其盐：In one embodiment of the present invention, the following compounds and their salts are preferred:

1.N-[4-氯-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；1. N-[4-chloro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide;

2.N-[4-氯-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；2. N-[4-chloro-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide ;

3.[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸丙酯；3. [1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-propyl carbamate;

4.N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-C-苯基-甲磺酰胺；4. N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-C-phenyl-methanesulfonamide;

5.4-氟-N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-苯甲酰胺；5. 4-fluoro-N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-benzamide;

6.N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；6. N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide;

7.N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-2-噻吩-2-基乙酰胺；7. N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-2-thiophen-2-ylacetamide;

8.N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；8. N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide;

9.3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-1，1-二异丙基脲；9. 3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-1,1-diisopropylurea;

10.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-吗啉-4-甲酰胺；10. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-morpholine-4-carboxamide;

11.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-吡咯烷-1-甲酰胺；11. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-pyrrolidine-1-carboxamide;

12.[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸2-苄氧基乙酯；12. [1-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-carbamic acid 2-benzyloxyethyl ester;

13.3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-1-甲基-1-丙基脲；13. 3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1-propylurea;

14.[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸叔丁酯；14. [1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-tert-butyl carbamate;

15.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-C-苯基-甲磺酰胺；15. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-C-phenyl-methanesulfonamide;

16.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁烷-1-磺酰胺；16. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butane-1-sulfonamide;

17.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-4-氟苯甲酰胺；17. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-4-fluorobenzamide;

18.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2，2-二甲基丙酰胺；18. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2,2-dimethylpropionamide;

19.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-苯氧基乙酰胺；19. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2-phenoxyacetamide;

20.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；20. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide;

21.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；21. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butanamide;

22.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-环戊烷甲酰胺；22. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-cyclopentanecarboxamide;

23.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-噻吩-2-基乙酰胺；23. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2-thiophen-2-ylacetamide;

24.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-异烟酰胺；24. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-isonicotinamide;

25.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-4-二甲基氨基苯甲酰胺；25. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-4-dimethylaminobenzamide;

26.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；26. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide;

27.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-IH-吲哚-5-基]-6-三氟甲基烟酰胺；27. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-6-trifluoromethylnicotinamide;

28.1-叔丁基-3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-脲；28. 1-tert-butyl-3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-urea;

29.1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-乙基脲；29. 1-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-ethylurea;

30.1-苄基-3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-脲；30. 1-Benzyl-3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-urea;

31.1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-苯乙基脲；31. 1-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-phenylethylurea;

32.1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-噻吩-2-基脲；32. 1-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-thiophen-2-ylurea;

33.1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-噻吩-3-基脲；33. 1-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-thiophen-3-ylurea;

34.2，2-二甲基-N-[6-硝基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-丙酰胺；34. 2,2-Dimethyl-N-[6-nitro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-propionamide;

35.N-[1-(5-氯噻吩-2-基甲基)-6-硝基-2，3-二氢-1H-吲哚-5-基]-2，2-二甲基丙酰胺；35. N-[1-(5-chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indol-5-yl]-2,2-dimethylpropane amides;

36.2-(4-氟苯基)-N-[6-硝基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；36.2-(4-fluorophenyl)-N-[6-nitro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-acetamide ;

37.N-[6-氨基-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；37. N-[6-amino-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide ;

38.N-[6-氨基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-2，2-二甲基丙酰胺；38. N-[6-amino-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-2,2-dimethylpropionamide;

39.N-[6-氨基-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2，2-二甲基丙酰胺；39. N-[6-amino-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2,2-dimethylpropionamide ;

40.N-[6-氨基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺，或40. N-[6-amino-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-B amides, or

41.N-[1-(5-氯噻吩-2-基甲基)-1H-吲哚-5-基]-3，3-二甲基丁酰胺。41. N-[1-(5-Chlorothiophen-2-ylmethyl)-1H-indol-5-yl]-3,3-dimethylbutanamide.

在本发明的另一个实施方案中，优选下列化合物和其盐：In another embodiment of the present invention, the following compounds and their salts are preferred:

1.N-[4-氯-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；1. N-[4-chloro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide;

2.N-[4-氯-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；2. N-[4-chloro-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide ;

3.[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸丙酯；3. [1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-propyl carbamate;

4.N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-C-苯基-甲磺酰胺；4. N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-C-phenyl-methanesulfonamide;

5.4-氟-N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-苯甲酰胺；5. 4-fluoro-N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-benzamide;

6.N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；6. N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide;

7.N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-2-噻吩-2-基乙酰胺；7. N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-2-thiophen-2-ylacetamide;

8.N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；8. N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide;

9.3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-1，1-二异丙基脲；9. 3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-1,1-diisopropylurea;

10.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-吗啉-4-甲酰胺；10. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-morpholine-4-carboxamide;

11.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-吡咯烷-1-甲酰胺；11. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-pyrrolidine-1-carboxamide;

12.[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸2-苄氧基乙酯；12. [1-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-carbamic acid 2-benzyloxyethyl ester;

13.3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-1-甲基-1-丙基脲；13. 3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1-propylurea;

14.[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸叔丁酯；14. [1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-tert-butyl carbamate;

15.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-C-苯基-甲磺酰胺；15. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-C-phenyl-methanesulfonamide;

16.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁烷-1-磺酰胺；16. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butane-1-sulfonamide;

17.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-4-氟苯甲酰胺；17. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-4-fluorobenzamide;

18.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2，2-二甲基丙酰胺；18. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2,2-dimethylpropionamide;

19.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-苯氧基乙酰胺；19. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2-phenoxyacetamide;

20.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；20. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide;

21.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；21. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butanamide;

22.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-环戊烷甲酰胺；22. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-cyclopentanecarboxamide;

23.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-噻吩-2-基乙酰胺；23. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2-thiophen-2-ylacetamide;

24.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-异烟酰胺；24. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-isonicotinamide;

25.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-4-二甲基氨基苯甲酰胺；25. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-4-dimethylaminobenzamide;

26.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；26. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide;

27.N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-6-三氟甲基烟酰胺；27. N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-6-trifluoromethylnicotinamide;

28.1-叔丁基-3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-脲；28. 1-tert-butyl-3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-urea;

29.1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-乙基脲；29. 1-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-ethylurea;

30.1-苄基-3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-脲；30. 1-Benzyl-3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-urea;

31.1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-苯乙基脲；31. 1-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-phenylethylurea;

32.1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-噻吩-2-基脲；32. 1-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-thiophen-2-ylurea;

33.1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-噻吩-3-基脲；33. 1-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-thiophen-3-ylurea;

34.[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸丙酯；34. [1-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-propyl carbamate;

35.2，2-二甲基-N-[6-硝基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-丙酰胺；35. 2,2-Dimethyl-N-[6-nitro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-propionamide;

36.N-[1-(5-氯噻吩-2-基甲基)-6-硝基-2，3-二氢-1H-吲哚-5-基]-2，2-二甲基丙酰胺；36. N-[1-(5-chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indol-5-yl]-2,2-dimethylpropane amides;

37.2-(4-氟苯基)-N-[6-硝基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；37.2-(4-fluorophenyl)-N-[6-nitro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-acetamide ;

38.N-[1-(5-氯噻吩-2-基甲基)-6-硝基-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；38. N-[1-(5-chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl )-acetamide;

39.N-[1-(5-氯噻吩-2-基甲基)-6-硝基-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；39. N-[1-(5-chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyl amides;

40.N-[6-氨基-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；40. N-[6-amino-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide ;

41.N-[6-氨基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-2，2-二甲基丙酰胺；41. N-[6-amino-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-2,2-dimethylpropionamide;

42.N-[6-氨基-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2，2-二甲基丙酰胺；42. N-[6-amino-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2,2-dimethylpropionamide ;

43.N-[6-氨基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；43. N-[6-Amino-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-B amides;

44.N-[6-氨基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；44. N-[6-amino-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide;

45.N-[6-氨基-1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；45. N-[6-amino-1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide;

46.N-[6-氨基-1-(3-氟-4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；46. N-[6-amino-1-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethyl Butanamide;

47.N-[1-(5-氯噻吩-2-基甲基)-1H-吲哚-5-基]-3，3-二甲基丁酰胺；47. N-[1-(5-chlorothiophen-2-ylmethyl)-1H-indol-5-yl]-3,3-dimethylbutanamide;

48.N-[6-溴-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；48. N-[6-bromo-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide;

49.N-[6-溴-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；49. N-[6-bromo-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide ;

50.N-[1-(4-氯苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；50. N-[1-(4-chlorobenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide;

51.3，3-二甲基-N-[1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；51. 3,3-Dimethyl-N-[1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-butanamide;

52.N-[1-(4-异丙基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；52. N-[1-(4-isopropylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide;

53.N-[1-(3-氟-4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；53. N-[1-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide;

54.N-[1-(6-氯苯并[1，3]二氧杂环戊烯-5-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；54. N-[1-(6-Chlorobenzo[1,3]dioxol-5-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3 , 3-dimethylbutanamide;

55.N-[1-(3，5-二甲基-1-苯基-1H-吡唑-4-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；55. N-[1-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-2,3-dihydro-1H-indol-5-yl]- 3,3-Dimethylbutanamide;

56.N-[1-(2-氯-5-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；56. N-[1-(2-chloro-5-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide;

57.N-{1-[5-(4-氯苯氧基)-1，3-二甲基-1H-吡唑-4-基甲基]-2，3-二氢-1H-吲哚-5-基}-3，3-二甲基丁酰胺；57. N-{1-[5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazol-4-ylmethyl]-2,3-dihydro-1H-indole -5-yl}-3,3-dimethylbutanamide;

58.3，3-二甲基-N-[1-(6-对甲苯氧基-吡啶-3-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；58. 3,3-Dimethyl-N-[1-(6-p-tolyloxy-pyridin-3-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butanamide;

59.N-{1-[6-(4-氯苯基硫基)-吡啶-3-基甲基]-2，3-二氢-1H-吲哚-5-基}-3，3-二甲基丁酰胺；59.N-{1-[6-(4-Chlorophenylsulfanyl)-pyridin-3-ylmethyl]-2,3-dihydro-1H-indol-5-yl}-3,3- Dimethylbutanamide;

60.N-{1-[6-(4-氰基苯氧基)-吡啶-3-基甲基]-2，3-二氢-1H-吲哚-5-基}-3，3-二甲基丁酰胺；60. N-{1-[6-(4-cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-1H-indol-5-yl}-3,3- Dimethylbutanamide;

61.3，3-二甲基-N-[1-(6-三氟甲基吡啶-3-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；61. 3,3-Dimethyl-N-[1-(6-trifluoromethylpyridin-3-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butanamide;

62.3，3-二甲基-N-[1-(3-甲基-苯并[b]噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；62.3,3-Dimethyl-N-[1-(3-methyl-benzo[b]thiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]- Butanamide;

63.N-[1-(6-氟-4H-苯并[1，3]二氧杂环己烯-8-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；63. N-[1-(6-fluoro-4H-benzo[1,3]dioxin-8-ylmethyl)-2,3-dihydro-1H-indol-5-yl ]-3,3-dimethylbutanamide;

64.3，3-二甲基-N-[1-(6-苯氧基吡啶-3-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；64. 3,3-Dimethyl-N-[1-(6-phenoxypyridin-3-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butanamide;

65.3，3-二甲基-N-[1-(3-甲基-5-苯基-异噁唑-4-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；65.3,3-Dimethyl-N-[1-(3-methyl-5-phenyl-isoxazol-4-ylmethyl)-2,3-dihydro-1H-indol-5-yl ]-Butanamide;

66.N-(1-苯并[b]噻吩-2-基甲基-2，3-二氢-1H-吲哚-5-基)-3，3-二甲基丁酰胺；66. N-(1-benzo[b]thiophen-2-ylmethyl-2,3-dihydro-1H-indol-5-yl)-3,3-dimethylbutanamide;

67.N-{1-[1-(4-氟苯基)-5-甲基-1H-吡唑-4-基甲基]-2，3-二氢-1H-吲哚-5-基}-3，3-二甲基丁酰胺；67. N-{1-[1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-ylmethyl]-2,3-dihydro-1H-indol-5-yl }-3,3-Dimethylbutanamide;

68.3，3-二甲基-N-[1-(5-甲基噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；68. 3,3-Dimethyl-N-[1-(5-methylthiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butanamide;

69.3，3-二甲基-N-[1-(4-吡咯-1-基-苄基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；69. 3,3-Dimethyl-N-[1-(4-pyrrol-1-yl-benzyl)-2,3-dihydro-1H-indol-5-yl]-butanamide;

70.N-[1-(4-氯苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；70. N-[1-(4-chlorobenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide;

71.2-(4-氟苯基)-N-[1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；71. 2-(4-fluorophenyl)-N-[1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-acetamide;

72.2-(4-氟苯基)-N-[1-(4-异丙基苄基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；72. 2-(4-fluorophenyl)-N-[1-(4-isopropylbenzyl)-2,3-dihydro-1H-indol-5-yl]-acetamide;

73.2-(4-氟苯基)-N-[1-(3-氟-4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；73. 2-(4-fluorophenyl)-N-[1-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-acetamide;

74.N-[1-(6-氯苯并[1，3]二氧杂环戊烯-5-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；74. N-[1-(6-Chlorobenzo[1,3]dioxol-5-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2 -(4-fluorophenyl)-acetamide;

75.N-[1-(3，5-二甲基-1-苯基-1H-吡唑-4-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；75. N-[1-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-2,3-dihydro-1H-indol-5-yl]- 2-(4-fluorophenyl)-acetamide;

76.N-[1-(2-氯-5-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；76. N-[1-(2-Chloro-5-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-B amides;

77.N-{1-[5-(4-氯苯氧基)-1，3-二甲基-1H-吡唑-4-基甲基]-2，3-二氢-1H-吲哚-5-基}-2-(4-氟苯基)-乙酰胺；77. N-{1-[5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazol-4-ylmethyl]-2,3-dihydro-1H-indole -5-yl}-2-(4-fluorophenyl)-acetamide;

78.N-{1-[6-(4-氰基苯氧基)-吡啶-3-基甲基]-2，3-二氢-1H-吲哚-5-基}-2-(4-氟苯基)-乙酰胺；78. N-{1-[6-(4-cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-1H-indol-5-yl}-2-(4 -fluorophenyl)-acetamide;

79.2-(4-氟苯基)-N-[1-(3-甲基-苯并[b]噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；79.2-(4-fluorophenyl)-N-[1-(3-methyl-benzo[b]thiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl ]-acetamide;

80.N-[1-(6-氟-4H-苯并[1，3]二氧杂环己烯-8-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；80. N-[1-(6-fluoro-4H-benzo[1,3]dioxin-8-ylmethyl)-2,3-dihydro-1H-indol-5-yl ]-2-(4-fluorophenyl)-acetamide;

81.2-(4-氟苯基)-N-[1-(6-苯氧基吡啶-3-基甲基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；81. 2-(4-fluorophenyl)-N-[1-(6-phenoxypyridin-3-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-acetamide;

82.N-(1-苯并[b]噻吩-2-基甲基-2，3-二氢-1H-吲哚-5-基)-2-(4-氟苯基)-乙酰胺；82. N-(1-benzo[b]thiophen-2-ylmethyl-2,3-dihydro-1H-indol-5-yl)-2-(4-fluorophenyl)-acetamide;

83.2-(4-氟苯基)-N-{1-[1-(4-氟苯基)-5-甲基-1H-吡唑-4-基甲基]-2，3-二氢-1H-吲哚-5-基}-乙酰胺；83.2-(4-fluorophenyl)-N-{1-[1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-ylmethyl]-2,3-dihydro- 1H-indol-5-yl}-acetamide;

84.2-(4-氟苯基)-N-[1-(5-甲基噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；和84. 2-(4-fluorophenyl)-N-[1-(5-methylthiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-acetamide; and

85.2-(4-氟苯基)-N-[1-(4-吡咯-1-基-苄基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺。85. 2-(4-Fluorophenyl)-N-[1-(4-pyrrol-1-yl-benzyl)-2,3-dihydro-1H-indol-5-yl]-acetamide.

根据一个实施方案，本发明涉及包含一种或多种药学可接受载体或稀释剂和式I化合物或其盐的药物组合物，式I中虚线、s、q、U、X、Z、Y、R1、R1’、R2和R3如上定义，因此任何的虚线、a、b、c、d、e、f、g、h、j、k、s、q、L、T、U、X、Z、Y、W、R1、R1’、R2、R3、R5、R6、R6’、R7、R7’、R8、R9、R9’、R10、R10’、R11、R12和R12’如式I定义。因而本发明的药物组合物可包含一种或多种式I化合物或其盐，例如一种式I化合物或其盐；或两种式I化合物或其盐；或三种式I化合物或其盐。According to one embodiment, the present invention relates to a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or diluents and a compound of formula I or a salt thereof, wherein dotted lines, s, q, U, X, Z, Y, R 1 , R 1' , R 2 and R 3 are as defined above, so any dashed line, a, b, c, d, e, f, g, h, j, k, s, q, L, T, U, X, Z, Y, W, R 1 , R 1' , R 2 , R 3 , R 5 , R 6 , R 6 ' , R 7 , R 7 ' , R 8 , R 9 , R 9' , R 10 , R 10' , R 11 , R 12 and R 12' are as defined in formula I. Thus the pharmaceutical composition of the present invention may comprise one or more compounds of formula I or salts thereof, for example one compound of formula I or salts thereof; or two compounds of formula I or salts thereof; or three compounds of formula I or salts thereof .

因而本发明提供了一种口服或胃肠外给药的药物组合物，所述药物组合物包含治疗有效量的至少一种式I化合物或其盐和一种或多种药学可接受载体或稀释剂。Thus the present invention provides a pharmaceutical composition for oral or parenteral administration comprising a therapeutically effective amount of at least one compound of formula I or a salt thereof and one or more pharmaceutically acceptable carriers or diluents agent.

在一方面，本发明的化合物可作为唯一治疗有效的化合物给药。In one aspect, the compounds of the invention may be administered as the only therapeutically effective compound.

在另一方面，本发明的化合物可作为联合治疗的一部分给药，也就是说本发明的化合物可与其他治疗有效(如具有抗惊厥性质)的化合物联合给药。这些具有抗惊厥性能的其他化合物的作用可包括但不限于对于如下体系的活性：In another aspect, the compounds of the present invention may be administered as part of combination therapy, that is to say the compounds of the present invention may be administered in combination with other therapeutically effective (eg possessing anticonvulsant properties) compounds. The effects of these other compounds with anticonvulsant properties may include, but are not limited to, activity on:

●离子通道，如钠、钾或钙通道；● ion channels, such as sodium, potassium or calcium channels;

●兴奋性氨基酸体系，例如NMDA受体的阻滞或调节；- Excitatory amino acid systems, such as blockade or regulation of NMDA receptors;

●抑制性神经递质体系，例如GABA释放的增强或GABA吸收的阻滞，或Inhibitory neurotransmitter systems, such as enhancement of GABA release or blockade of GABA uptake, or

●膜稳定作用。• Membrane stabilization.

目前的抗惊厥药物包括但不限于噻加宾、卡马西平、丙戊酸钠、拉莫三嗪、加巴喷丁、普瑞巴林、乙琥胺、左乙拉西坦、苯妥英、托吡酯、唑尼沙胺以及苯并二氮杂类和巴比妥盐类。Current anticonvulsants include but are not limited to tiagabine, carbamazepine, sodium valproate, lamotrigine, gabapentin, pregabalin, ethosuximide, levetiracetam, phenytoin, topiramate, zonisar Amines and benzodiazepines and barbiturates.

在一个方面，已发现本发明的化合物对KCNQ家族(特别是KCNQ2亚型)的钾离子通道有效。In one aspect, compounds of the invention have been found to be effective on potassium ion channels of the KCNQ family, particularly the KCNQ2 subtype.

在一个实施方案中，本发明涉及本发明的一种或多种化合物在治疗方法中的用途。被预防、治疗或抑制的疾病或症状对在钾离子通道(如KCNQ家族钾离子通道)中增加的离子流动反应。这些疾病或症状优选中枢神经系统的疾病或症状。In one embodiment, the invention relates to the use of one or more compounds of the invention in a method of therapy. The disease or condition to be prevented, treated or inhibited responds to increased ion flux in potassium ion channels, such as KCNQ family potassium ion channels. These diseases or symptoms are preferably diseases or symptoms of the central nervous system.

认为本发明的化合物可用于增加在哺乳动物(如人)的电压依赖钾离子通道中的离子流。The compounds of the invention are believed to be useful for increasing ion flux in voltage-dependent potassium ion channels in mammals such as humans.

认为本发明的化合物可用于预防、治疗或抑制对钾离子通道(如KCNQ家族钾离子通道)中离子流动增加敏感的疾病或症状。这些疾病或症状优选中枢神经系统的疾病或症状。The compounds of the present invention are believed to be useful in the prevention, treatment or inhibition of diseases or conditions that are sensitive to increased ion flow in potassium ion channels such as the KCNQ family of potassium ion channels. These diseases or symptoms are preferably diseases or symptoms of the central nervous system.

因而认为本发明的化合物可用于预防、治疗或抑制病症或疾病如癫痫、神经疼痛和偏头痛、焦虑症和神经变性疾病。The compounds of the present invention are thus considered useful for preventing, treating or inhibiting conditions or diseases such as epilepsy, neuropathic pain and migraine, anxiety and neurodegenerative diseases.

因而，认为本发明的化合物可用于预防、治疗或抑制疾病或病症如惊厥、癫痫、焦虑症、神经痛和神经变性疾病。Thus, the compounds of the present invention are believed to be useful in the prevention, treatment or suppression of diseases or conditions such as convulsions, epilepsy, anxiety, neuralgia and neurodegenerative diseases.

因此根据本发明一个特别的实施方案，认为本发明的化合物可用于预防、治疗或抑制癫痫发作症如惊厥、癫痫和癫痫持续状态。Thus, according to a particular embodiment of the invention, the compounds of the invention are considered useful for the prevention, treatment or suppression of epileptic seizure disorders such as convulsions, epilepsy and status epilepticus.

在一个实施方案中，认为本发明的化合物可用于预防、治疗和抑制惊厥。In one embodiment, the compounds of the present invention are believed to be useful in the prevention, treatment and inhibition of convulsions.

在另一个实施方案中，认为本发明的化合物可用于预防、治疗和抑制癫痫、癫痫综合症和癫痫发作。In another embodiment, the compounds of the present invention are believed to be useful in the prevention, treatment and suppression of epilepsy, epileptic syndromes and seizures.

在再一个实施方案中，认为本发明的化合物用于预防、治疗和抑制焦虑症(如焦虑症)和与以下情况相关的疾病和病症：惊恐发作、广场恐怖症、带有广场恐怖症的恐惧症、不带广场恐怖症的恐惧症、无恐惧症史的广场恐怖症、特异性恐怖症、社交恐怖和其他特异性恐怖症、强迫观念与行为症、创伤后应激症、急性应激反应、广泛性焦虑症、起因于全身健康状况的焦虑症、物质诱发的焦虑症、分离焦虑症、适应性障碍、行为焦虑、疑病症、起因于全身健康状况的焦虑症和物质诱发的焦虑症和其他未加说明的焦虑症。In yet another embodiment, the compounds of the present invention are considered useful in the prevention, treatment and inhibition of anxiety disorders (such as anxiety disorders) and diseases and conditions associated with: panic attacks, agoraphobia, phobias with agoraphobia phobia, phobia without agoraphobia, agoraphobia without history of phobia, specific phobia, social phobia and other specific phobias, obsessive-compulsive and behavioral disorders, post-traumatic stress disorder, acute stress response , generalized anxiety disorder, anxiety disorder due to a general health condition, substance-induced anxiety disorder, separation anxiety disorder, adjustment disorder, behavioral anxiety, hypochondria, anxiety disorder due to a general health condition, and substance-induced anxiety disorder and Other unspecified anxiety disorders.

在再一个实施方案中，认为本发明的化合物可用于预防、治疗和抑制焦虑症如焦虑、广泛性焦虑症、恐慌性焦虑症、强迫观念与行为症、社会恐怖、行为焦虑、创伤后应激症、急性应激反应、适应性障碍、疑病症、分离焦虑症、广场恐怖症、特异性焦虑、起因于全身健康状况的焦虑症和物质诱发的焦虑症。In yet another embodiment, the compounds of the present invention are considered useful in the prevention, treatment and suppression of anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety disorder, obsessive-compulsive disorder, social phobia, behavioral anxiety, post-traumatic stress anxiety disorder, acute stress response, adjustment disorder, hypochondria, separation anxiety disorder, agoraphobia, specific anxiety, anxiety disorders arising from general health conditions, and substance-induced anxiety disorders.

在再一个实施方案中，还认为本发明的化合物可用于预防、治疗和抑制神经痛和偏头痛疾病，如异常性疼痛、痛觉过敏性疼痛、幻痛、与糖尿病性神经病相关的神经痛以及与偏头痛相关的神经痛。在再一个实施方案中，认为本发明的化合物可用于预防、治疗和抑制神经变性的疾病如阿尔茨海默氏病；亨廷顿舞蹈病；多发性硬化；肌萎缩性侧索硬化症；克罗伊茨费尔特-雅各布病；帕金森氏病；AIDS-诱发的脑病或由风疹病毒、疱疹病毒、疏螺旋体属以及未知的病原体感染引起的脑病；外伤引起的神经变性；如在药物戒毒过程或由于醉酒引起的神经元兴奋过度状态；和周围神经系统的变性疾病，如多发性神经病和多神经炎。In yet another embodiment, the compounds of the present invention are also believed to be useful in the prevention, treatment and inhibition of neuropathic and migraine disorders such as allodynia, hyperalgesic pain, phantom pain, neuralgia associated with diabetic neuropathy and Migraine-related neuralgia. In yet another embodiment, the compounds of the present invention are considered useful in the prevention, treatment and inhibition of neurodegenerative diseases such as Alzheimer's disease; Huntington's disease; multiple sclerosis; amyotrophic lateral sclerosis; Zfeldt-Jakob disease; Parkinson's disease; AIDS-induced encephalopathy or encephalopathy caused by rubella virus, herpes virus, Borrelia, and unknown pathogens; trauma-induced neurodegeneration; as in drug withdrawal process or state of hyperexcitability of neurons due to intoxication; and degenerative diseases of the peripheral nervous system, such as polyneuropathy and polyneuritis.

在再一个实施方案中，认为本发明的化合物可用于预防、治疗和抑制神经变性的疾病如阿尔茨海默氏病；亨廷顿舞蹈病；多发性硬化；肌萎缩性侧索硬化症；克罗伊茨费尔特-雅各布病；帕金森氏病；AIDS-诱发的脑病或由风疹病毒、疱疹病毒、疏螺旋体属以及未知的病原体感染引起的脑病；外伤引起的神经变性。In yet another embodiment, the compounds of the present invention are considered useful in the prevention, treatment and inhibition of neurodegenerative diseases such as Alzheimer's disease; Huntington's disease; multiple sclerosis; amyotrophic lateral sclerosis; Zfeldt-Jakob disease; Parkinson's disease; AIDS-induced encephalopathy or encephalopathy caused by infection with rubella virus, herpes virus, Borrelia, and unknown pathogens; trauma-induced neurodegeneration.

在再一个实施方案中，认为本发明的化合物可用于预防、治疗和抑制如在药物戒毒过程或由于醉酒引起的神经元兴奋过度状态。In yet another embodiment, the compounds of the present invention are believed to be useful in the prevention, treatment and suppression of neuronal hyperexcitability states such as during drug withdrawal or due to intoxication.

本发明提供了在一个或多个如下试验中显示有效的化合物：The present invention provides compounds that have been shown to be effective in one or more of the following assays:

●“通过KCNQ2通道的相对流量”，该试验用于测定化合物在目标通道的效能；● "Relative flux through the KCNQ2 channel", this test is used to determine the potency of the compound in the target channel;

●“最大电击”，该试验用于测定通过电击方式的非特异性CNS刺激诱发的癫痫；● "Maximum Shock", a test for the determination of seizures induced by nonspecific CNS stimulation by means of an electric shock;

●“毛果芸香碱诱发的癫痫”，用现有的抗癫痫药物难以治疗毛果芸香碱诱发的癫痫，因此考虑一个“耐药癫痫”模型；● "Pitlocarpine-induced epilepsy", it is difficult to treat pilocarpine-induced epilepsy with existing antiepileptic drugs, so consider a "drug-resistant epilepsy" model;

●“电癫痫阈值试验”和“化学癫痫阈值试验”，这些模型测定了癫痫开始的阈值，因此可作为检测各个化合物是否延迟了癫痫的开始的模型；● "Electrical Seizure Threshold Test" and "Chemical Seizure Threshold Test", these models determine the threshold of seizure onset and can therefore be used as models to test whether individual compounds delay the onset of seizures;

●“杏仁核点燃诱发”，该试验用于测定疾病进展，由于这些动物接受了更多的刺激，与正常的动物相比，这种模型中的癫痫更严重。• "Amygdala Ignition Provoked", an assay used to measure disease progression, since these animals received more stimulation, seizures were more severe in this model compared to normal animals.

根据本发明的一个特别方面，所述化合物具有KCNQ2活性，采用下述的试验“通过KCNQ2通道的相对流量”测定，EC50小于15000nM，例如小于10000nM。According to a particular aspect of the invention, said compound has KCNQ2 activity with an EC50 of less than 15000 nM, such as less than 10000 nM, as determined using the assay "Relative flux through KCNQ2 channels" described below.

根据本发明的另一个特别方面，所述化合物具有KCNQ2活性，采用下述的试验“通过KCNQ2通道的相对流量”测定，EC50小于2000nM，例如小于1500nM。According to another particular aspect of the invention, said compound has KCNQ2 activity with an EC50 of less than 2000 nM, such as less than 1500 nM, as determined by the assay "relative flux through KCNQ2 channels" described below.

根据本发明的再一个特别方面，所述化合物具有KCNQ2活性，采用下述的试验“通过KCNQ2通道的相对流量”测定，EC50小于200nM，例如小于150nM。According to yet another particular aspect of the invention, said compound has KCNQ2 activity, as determined by the assay "relative flux through KCNQ2 channels" described below, with an EC50 of less than 200 nM, such as less than 150 nM.

根据本发明的一个特别方面，在如下所述的“最大电击”试验中所述化合物的ED50小于15mg/kg。According to a particular aspect of the invention, said compound has an ED50 of less than 15 mg/kg in the "Maximum Electric Shock" test as described below.

根据本发明的一个特别方面，在如下所述的“最大电击”试验中所述化合物的ED50小于5mg/kg。According to a particular aspect of the invention, said compound has an ED50 of less than 5 mg/kg in the "Maximum Electric Shock" test as described below.

根据本发明的一个特别方面，在如下所述的“电癫痫阈值试验”和“化学癫痫阈值试验”中所述化合物的ED50小于5mg/kg。According to a particular aspect of the invention, said compound has an ED50 of less than 5 mg/kg in the "Electrical Seizure Threshold Test" and "Chemical Seizure Threshold Test" as described below.

某些化合物几乎没有副作用或仅有临床上不显著的副作用。因此某些化合物在该化合物的无需镇静、低温和失调共济的模型中进行试验。Certain compounds have few or only clinically insignificant side effects. Certain compounds are therefore tested in models of the compound that do not require sedation, hypothermia, and dysregulation.

某些化合物具有抗惊厥效果和副反应(例如通过在旋转杆上的行为测定的运动能力伤害或运动失调反应)之间的较大治疗指数。这意味着在可见副反应之前，可预期所述化合物可被患者很好耐受，因而允许高的剂量。因此，可预期具有很好的治疗耐用受性且可以高剂量给药，使得对于那些采用其他药物会产生副反应的患者来说更具疗效。Certain compounds have a large therapeutic index between anticonvulsant effects and side effects such as impairment of motor performance or ataxia responses as measured by behavior on a rotarod. This means that the compound can be expected to be well tolerated by patients before side effects are visible, thus allowing high dosages. Therefore, it is expected to be well tolerated for treatment and can be administered in high doses, making it more effective for patients who have side effects from other drugs.

                         定义Definition

术语杂原子是指氮、氧或硫原子。The term heteroatom refers to nitrogen, oxygen or sulfur atoms.

卤素是指氟、氯、溴或碘。Halogen means fluorine, chlorine, bromine or iodine.

表述C1-6-烷(烯/炔)基和C1-6-(烷/烯/炔)基是指C1-6-烷基、C2-6-烯基或C2-6-炔基。术语C1-6-烷基是指支化的或非支化的烷基，该烷基包含1至6个碳原子，包括但不限于甲基、乙基、1-丙基、2-丙基、1-丁基、2-丁基、2-甲基-2-丙基和2-甲基-1-丙基。同样地，C2-6-烯基和C2-6-炔基分别表示具有2至6个碳原子的这类基团，分别包括一个双键和一个三键，包括但不限于乙烯基、丙烯基、丁烯基、乙炔基、丙炔基和丁炔基。The expressions C 1-6 -alk(en/yn)yl and C 1-6 -(alk/en/yn)yl refer to C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 - Alkynyl. The term C 1-6 -alkyl means a branched or unbranched alkyl group containing 1 to 6 carbon atoms including but not limited to methyl, ethyl, 1-propyl, 2-propanyl 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl. Likewise, C 2-6 -alkenyl and C 2-6 -alkynyl denote such groups having 2 to 6 carbon atoms, respectively, including one double bond and one triple bond, including but not limited to vinyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

表述C1-3-烷(烯/炔)基是指C1-3-烷基、C2-3-烯基或C2-3-炔基。术语C1-3-烷基是指支化的或非支化的烷基，该烷基包含1至3个碳原子，包括但不限于甲基、乙基、1-丙基、2-丙基。同样地，C2-3-烯基和C2-3-炔基分别表示具有2至3个碳原子的这类基团，分别包括一个双键和一个三键，包括但不限于乙烯基、1-丙烯基、2-丙烯基、3-丙烯基、乙炔基、1-丙炔基和3-丙炔基。The expression C 1-3 -alk(en/yn)yl refers to C 1-3 -alkyl, C 2-3 -alkenyl or C 2-3 -alkynyl. The term C 1-3 -alkyl refers to a branched or unbranched alkyl group containing 1 to 3 carbon atoms, including but not limited to methyl, ethyl, 1-propyl, 2-propanyl base. Likewise, C 2-3 -alkenyl and C 2-3 -alkynyl denote such groups having 2 to 3 carbon atoms, respectively, including one double bond and one triple bond, including but not limited to vinyl, 1-propenyl, 2-propenyl, 3-propenyl, ethynyl, 1-propynyl and 3-propynyl.

表述C3-8-环烷(烯)基和C3-8-环(烷/烯)基是指C3-8-环烷基或环烯基。术语C3-8-环烷基表示具有3至8个碳原子的单环或二环碳环，包括但不限于环丙基、环丁基、环戊基、环己基等。术语C3-8-环烯基表示具有3至8个碳原子且包括一个双键的单环或二环碳环。The expressions C 3-8 -cycloalk(en)yl and C 3-8 -cyclo(alk/en)yl refer to C 3-8 -cycloalkyl or cycloalkenyl. The term C 3-8 -cycloalkyl denotes a monocyclic or bicyclic carbocycle having 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term C 3-8 -cycloalkenyl denotes a monocyclic or bicyclic carbocycle having 3 to 8 carbon atoms and including one double bond.

表述C3-6-环烷(烯)基和C3-6-环(烷/烯)是指C3-6-环烷基或环烯基。术语C3-6-环烷基表示具有3至6个碳原子的单环或二环碳环，包括但不限于环丙基、环丁基、环戊基、环己基等。The expressions C 3-6 -cycloalk(en)yl and C 3-6 -cyclo(alk/en) refer to C 3-6 -cycloalkyl or cycloalkenyl. The term C 3-6 -cycloalkyl denotes a monocyclic or bicyclic carbocycle having 3 to 6 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

术语杂环烷(烯)基表示单环或二环体系，其中所述环由4至8个选自2至7个碳原子和1或2个选自N、S或O的杂原子的原子形成。The term heterocycloalk(en)yl denotes a monocyclic or bicyclic ring system in which the ring consists of 4 to 8 atoms selected from 2 to 7 carbon atoms and 1 or 2 heteroatoms selected from N, S or O form.

当两个取代基与其连接的碳原子一起形成任选包含1或2个杂原子的3至8元饱和或不饱和环时，单环体系由3至8个选自1至8个碳原子和0至2个选自N、S或O的杂原子的原子形成。这些环体系的实例为环丙基、环丁基、环戊基、环己基。When two substituents form a 3 to 8 membered saturated or unsaturated ring optionally containing 1 or 2 heteroatoms together with the carbon atoms to which they are attached, the monocyclic ring system consists of 3 to 8 members selected from 1 to 8 carbon atoms and 0 to 2 atoms of heteroatoms selected from N, S or O are formed. Examples of such ring systems are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

术语卤代-C1-6-烷(烯/炔)基表示被一个或多个卤原子取代的C1-6-烷(烯/炔)基，包括但不限于三氟甲基。同样地，卤代-C3-8-环烷(烯)基表示被一个或多个卤原子取代的C3-8-环烷(烯)基，卤代杂环烷(烯)基表示被一个或多个卤原子取代的杂环烷(烯)基。The term halo-C 1-6 -alk(en/yn)yl denotes C 1-6 -alk(en/yn)yl substituted by one or more halogen atoms, including but not limited to trifluoromethyl. Likewise, halo-C 3-8 -cycloalk(en)yl means C 3-8 -cycloalk(en)yl substituted by one or more halogen atoms, haloheterocycloalk(en)yl means substituted by A heterocycloalk(en)yl group substituted with one or more halogen atoms.

术语NR12R12’-C1-6-烷(烯/炔)基表示被NR12R12’取代的C1-6-烷(烯/炔)基。术语NR12R12’-C3-8-环烷(烯)基表示被NR12R12’取代的C3-8-环烷(烯)基。术语NR12R12’-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基表示被NR12R12’取代的C3-8-环烷(烯)基-C1-6-烷(烯/炔)基。当NR12R12’-C1-6-烷(烯/炔)基、NR12R12’-C3-8-环烷(烯)基和NR12R12’-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基中的任一个被任选取代时，C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基中的任一个任选被一个或多个独立地为C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基或芳基的取代基取代。The term NR 12 R 12' -C 1-6 -alk(en/yn)yl denotes C 1-6 -alk(en/yn)yl substituted by NR 12 R 12' . The term NR 12 R 12' -C 3-8 -cycloalk(en)yl denotes C 3-8 -cycloalk(en)yl substituted by NR 12 R 12' . The term NR 12 R 12' -C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl denotes C 3-8 -cycloalk(en) substituted by NR 12 R 12' -C 1-6 -alk(en/yn)yl. When NR 12 R 12' -C 1-6 -alk(en/yn)yl, NR 12 R 12' -C 3-8 -cycloalk(en)yl and NR 12 R 12' -C 3-8 -cyclo When any of alk(en)yl-C 1-6 -alk(en/yn)yl is optionally substituted, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en) ) group, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn) group is optionally replaced by one or more independently C 1-6 -alk(en/ Alkynyl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl or aryl substituents.

本文中使用的术语酰基是指甲酰基、C1-6-烷(烯/炔)基羰基、C3-8-环烷(烯)基羰基、芳基-羰基、芳基-C1-6-烷(烯/炔)基羰基或C3-8-环烷(烯)基-C1-6-烷(烯/炔)基-羰基，其中C1-6-烷(烯/炔)基、C3-8-环烷(烯)基和芳基如上定义。The term acyl as used herein is formyl, C 1-6 -alk(en/yn)ylcarbonyl, C 3-8 -cycloalk(en)ylcarbonyl, aryl-carbonyl, aryl-C 1-6 - Alk(en/yn)ylcarbonyl or C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl-carbonyl, wherein C 1-6 -alk(en/yn)yl, C 3-8 -Cycloalk(en)yl and aryl are as defined above.

当两个取代基与其连接的氮原子一起形成任选包含1、2或3个其他杂原子的4至8元饱和或不饱和环时，单环体系由4至8个选自氮原子、1至7个碳原子和0至3个选自N、S或O的杂原子的原子形成。这种环体系的实例为氮杂环丁烷、β-内酰胺(lactame)、吡咯烷、哌啶、哌嗪、吗啉、吡咯、噁唑烷、噻唑烷、咪唑烷、氮杂环丁烷、β-内酰胺、四唑和吡唑。When two substituents form a 4 to 8 membered saturated or unsaturated ring optionally containing 1, 2 or 3 other heteroatoms together with the nitrogen atom to which they are attached, the monocyclic ring system consists of 4 to 8 members selected from nitrogen atoms, 1 to 7 carbon atoms and 0 to 3 heteroatoms selected from N, S or O. Examples of such ring systems are azetidine, β-lactame, pyrrolidine, piperidine, piperazine, morpholine, pyrrole, oxazolidine, thiazolidine, imidazolidine, azetidine , β-lactams, tetrazoles and pyrazoles.

当两个邻近取代基与其连接的芳基一起形成任选包含一个或两个杂原子的4至8元环时，环体系由4至8个选自3至8个碳原子和0至2个选自N、S或O的杂原子的原子形成。两个邻近的取代基可一起形成：When two adjacent substituents are taken together with the aryl to which they are attached to form a 4 to 8 membered ring optionally containing one or two heteroatoms, the ring system consists of 4 to 8 members selected from 3 to 8 carbon atoms and 0 to 2 Atoms of heteroatoms selected from N, S or O are formed. Two adjacent substituents can be formed together:

(CH2)n’‘-CH2-、-CH＝CH-(CH2)m’‘-、-CH2-CH＝CH-(CH2)p’‘-、-CH＝CH-CH＝CH-、-(CH2)n’‘-O-、-O-(CH2)m’‘-O-、-CH2-O-(CH2)p’‘-O-、-CH2-O-CH2-O-CH2-、-(CH2)n’‘-S-、-S-(CH2)m’‘-S-、-CH2-S-(CH2)p’‘-S-、-CH2-S-CH2-S-CH2-、-(CH2)n’‘-NH-、-NH-(CH2)m’‘-NH-、-CH2-NH-(CH2)p’‘-NH-、-CH＝CH-NH-、-O-(CH2)m’‘-NH-、-CH2-O-(CH2)p’‘-NH-或-O-(CH2)p’‘-NH-CH2-、-S-(CH2)m’‘-NH-、-N＝CH-NH-、-N＝CH-O-或-N＝CH-S-，其中m’‘为1、2或3，n’‘为2、3或4和p’‘为1或2。(CH 2 ) n'' -CH 2 -, -CH=CH-(CH 2 ) m'' -, -CH 2 -CH=CH-(CH 2 ) p'' -, -CH=CH-CH= CH-, -(CH 2 ) n'' -O-, -O-(CH 2 ) m'' -O-, -CH 2 -O-(CH 2 ) p'' -O-, -CH 2 - O-CH 2 -O-CH 2 -, -(CH 2 ) n'' -S-, -S-(CH 2 ) m'' -S-, -CH 2 -S-(CH 2 ) p'' -S-, -CH 2 -S-CH 2 -S-CH 2 -, -(CH 2 ) n'' -NH-, -NH-(CH 2 ) m'' -NH-, -CH 2 -NH -(CH 2 ) p'' -NH-, -CH=CH-NH-, -O-(CH 2 ) m'' -NH-, -CH 2 -O-(CH 2 ) p'' -NH- or -O-(CH 2 ) p'' -NH-CH 2 -, -S-(CH 2 ) m'' -NH-, -N=CH-NH-, -N=CH-O- or -N =CH-S-, wherein m'' is 1, 2 or 3, n'' is 2, 3 or 4 and p'' is 1 or 2.

术语芳基是指任选取代的5至10个碳原子的芳族体系，其中0、1、2、3或4个碳原子可被独立地选自N、S或O的杂原子取代。这些芳基的实例为任选取代的苯基、任选取代的萘基、任选取代的吡啶、任选取代的吡咯、任选取代的嘧啶、任选取代的喹啉、任选取代的吲哚、任选取代的噻吩、任选取代的呋喃、任选取代的噻唑和任选取代的噁唑。芳基可被一个或多个独立地为羟基、卤素、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基氧基、C3-8-烷(烯/炔)基氧基、酰基、硝基或氰基、-CO-NH-C1-6-烷(烯/炔)基、-CO-N(C1-6-烷(烯/炔)基)2、-NH2、-NH-C1-6-烷(烯/炔)基、-N(C1-6-烷(烯/炔)基)2、-S-C1-6-烷(烯/炔)基、-SO2-C1-6-烷(烯/炔)基、-SO2N(C1-6-烷(烯/炔)基)2和-SO2NH-C1-6-烷(烯/炔)基的取代基取代；或两个邻近取代基与其连接的芳基一起形成任选包含一个或两个杂原子的4至8元的饱和或未饱和环。The term aryl refers to an optionally substituted aromatic system of 5 to 10 carbon atoms, wherein 0, 1, 2, 3 or 4 carbon atoms may be replaced by heteroatoms independently selected from N, S or O. Examples of such aryl groups are optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridine, optionally substituted pyrrole, optionally substituted pyrimidine, optionally substituted quinoline, optionally substituted ind Indole, optionally substituted thiophene, optionally substituted furan, optionally substituted thiazole, and optionally substituted oxazole. Aryl can be replaced by one or more independently of hydroxyl, halogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en) Base-C 1-6 -alk(en/yn)yl, Halo-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 -alk(en/yn)yloxy, acyl, nitro or cyano, -CO-NH-C 1-6 -alk(en/yn)yl, -CO-N(C 1-6 -alk(en) /Alkynyl) 2 , -NH 2 , -NH-C 1-6 -alk(en/yn)yl, -N(C 1-6 -alk(en/yn)yl) 2, -SC 1-6 -Alk(en/yn)yl, -SO 2 -C 1-6 -alk(en/yn)yl, -SO 2 N(C 1-6 -alk(en/yn)yl) 2 and -SO 2 NH Substituent substitution of -C 1-6 -alk(en/yn)yl; or two adjacent substituents together with the aryl to which it is attached form a 4 to 8 membered saturated or unsaturated optionally containing one or two heteroatoms ring.

术语C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、C1-6-烷(烯/炔)基-杂环烷(烯)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8环烷(烯)基、芳基-杂环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基-C1-6-烷(烯/炔)基-杂环烷(烯)基、C1-6-烷(烯/炔)基氧基、C2-6-烯基氧基、C2-6-炔基氧基、C3-8-环烷(烯)基氧基、C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基氧基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基氧基-C3-8-环烷(烯)基、C1-6-烷(烯/炔)基氧基-杂环烷(烯)基、芳基-氧基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基羰基、C3-8-烷(烯/炔)基羰基、芳基-羰基、芳基-C1-6-烷(烯/炔)基羰基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基羰基、-CO-C1-6-烷(烯/炔)基、-S-C1-6-烷(烯/炔)基、-SO2-C1-6-烷(烯/炔)基和-SO2O-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基氧基-羰基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基氧基-羰基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基氧基-羰基-C1-6-烷(烯/炔)基、酰基、酰基-C1-6-烷(烯/炔)基、酰基-C3-8-环烷(烯)基、酰基-杂环烷(烯)基、酰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、酰基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、酰基-C1-6-烷(烯/炔)基-杂环烷(烯)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-杂环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、羟基-C1-6-烷(烯/炔)基-杂环烷(烯)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代杂环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、卤代-C1-6-烷(烯/炔)基-杂环烷(烯)基、卤代-C1-6-烷(烯/炔)基-芳基、卤代-C3-8-环烷(烯)基-芳基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基-芳基、卤代-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基-芳基、卤代-杂环烷(烯)基-芳基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-杂环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、氰基-C1-6-烷(烯/炔)基-杂环烷(烯)基等表示这类基团，其中C1-6-烷(烯/炔)基、C2-6-烯基、C2-6-炔基、C3-8-环烷(烯)基、杂环烷(烯)基、芳基、氰基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代杂环烷(烯)基和酰基如上定义。The term C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl , C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 cycloalkane (en)yl, aryl-heterocycloalk(en)yl, aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl-C 1- 6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, aryl-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, C 1-6 -alk(en/yn)yloxy, C 2-6 -alkenyloxy, C 2-6 -alkynyloxy, C 3-8 -cycloalk(en)yloxy, C 1-6 - Alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yloxy-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy-C 3-8 -cycloalk(en)yl, C 1-6 -alk(en/yn)yloxy-heterocycloalk(en)yl, Aryl-oxy-C 1-6 -alk(en/yn)yl, Aryl-C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)ylcarbonyl, C 3-8 -alk(en/yn)ylcarbonyl, aryl-carbonyl, aryl-C 1-6 -alk(en/yn)ylcarbonyl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)ylcarbonyl, -CO-C 1-6 -alk(en/yn)yl, -SC 1-6 -alk( En/yn)yl, -SO 2 -C 1-6 -alk(en/yn)yl and -SO 2 OC 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn) Oxy-carbonyl-C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, C 3 -8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, acyl, acyl-C 1-6 -alk (en/alkyn)yl, acyl-C 3-8 -cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C 3-8 -cycloalk(en)yl-C 1-6 - Alk(en/yn)yl, acyl-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, acyl-C 1-6 -alk(en/yn)yl- Heterocycloalk(en)yl, Hydroxy-C 1-6 -alk(en/yn)yl, Hydroxy-C 3-8 -cycloalk(en)yl, Hydroxy-heterocycloalk(en)yl, Hydroxy-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl , Hydroxy-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, Halo-C 1-6 -alk(en/yn)yl, Halo-C 3-8 -cycloalkane (en)yl, haloheterocycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -Alk(en/yn)yl-C 3-8 -cycloalk(en)yl, halo-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, halo-C 1 -6 -alk(en/yn)yl-aryl, halo-C 3-8 -cycloalk(en)yl-aryl, halo-C 3-8 -cycloalk(en)yl-C 1- 6 -alk(en/yn)yl-aryl, halo-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl-aryl, halo-heterocycloalkane (en)yl-aryl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl, cyano-heterocycloalk(en)yl, Cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl-C 3-8 -cyclo Alk(en)yl, cyano-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl and the like represent such groups, wherein C 1-6 -alk(en/yn)yl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalk(en)yl, heterocycloalk(en)yl, aryl, cyano, halo-C 1-6 - Alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, haloheterocycloalk(en)yl and acyl are as defined above.

本发明的盐优选药学上可接受的盐。这些盐包括药学上可接受的酸加成盐、药学上可接受的金属盐、铵盐、烷基化的铵盐。The salts of the present invention are preferably pharmaceutically acceptable salts. These salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium salts, alkylated ammonium salts.

本发明的药学上可接受的盐优选为酸加成盐。本发明的酸加成盐优选为本发明的化合物与无毒酸形成的药学上可接受的盐。酸加成盐包括无机酸和有机酸的盐。合适的无机酸的代表性实例包括盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、磷酸和硝酸等。合适的有机酸的代表性实例包括甲酸、乙酸、三氯乙酸、三氟乙酸、丙酸、苯甲酸、肉桂酸、柠檬酸、富马酸、羟基乙酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、草酸、苦味酸、丙酮酸、水杨酸、琥珀酸、乙磺酸、酒石酸、抗坏血酸、双羟萘酸、葡糖酸、柠康酸、天冬氨酸、硬脂酸、棕榈酸、EDTA、羟基乙酸、对氨基苯甲酸、谷氨酸、双亚甲基水杨酸(bis-methylene salicylic acid)、甲磺酸、乙二磺酸、衣康酸、苯磺酸、对甲苯磺酸、乙酸茶碱以及8-卤代茶碱(例如8-溴茶碱等)。更多的药学上可接受的无机或有机酸加成盐的实例列于J.Pharm.Sci.1977，66，2中，其通过引用结合在本文中。The pharmaceutically acceptable salts of the present invention are preferably acid addition salts. The acid addition salts of the present invention are preferably pharmaceutically acceptable salts of the compounds of the present invention with non-toxic acids. Acid addition salts include salts of inorganic and organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric, and nitric acids, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, propionic acid, Diacid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid , palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, bis-methylene salicylic acid (bis-methylene salicylic acid), methanesulfonic acid, ethanedisulfonic acid, itaconic acid, benzenesulfonic acid, p-toluenesulfonic acid, theophylline acetate, and 8-halogenated theophylline (such as 8-bromotheophylline, etc.). Further examples of pharmaceutically acceptable inorganic or organic acid addition salts are listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.

金属盐的实例包括锂、钠、钾、镁盐等。Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like.

铵盐和烷基化铵盐的实例包括铵、甲基-、二甲基-、三甲基-、乙基-、羟乙基-、二乙基-、正丁基-、仲丁基-、叔丁基-、四甲基铵盐等。Examples of ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl- , tert-butyl-, tetramethylammonium salt, etc.

另一种药学上可接受的酸加成盐为该化合物可形成的氢化物。Another pharmaceutically acceptable acid addition salt is the hydride that this compound can form.

本发明的化合物可具有一个或多个手性中心并且任何光学异构体，如分离的、纯的或部分纯化的光学异构体或其外消旋混合物包括在本发明范围内。The compounds of the present invention may possess one or more chiral centers and any optical isomers, such as isolated, pure or partially purified optical isomers or racemic mixtures thereof, are included within the scope of the present invention.

此外，当分子中存在双键或全部或部分饱和的环体系时，可形成几何异构体。任何几何异构体，如分离的、纯的或部分纯化的几何异构体或其混合物都包括在本发明的范围。同样，具有旋转限制的键的分子可形成几何异构体。这些也包括在本发明的范围。In addition, geometric isomers may form when double bonds or fully or partially saturated ring systems are present in the molecule. Any geometric isomers, such as isolated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the present invention. Likewise, molecules with rotationally restricted bonds can form geometric isomers. These are also included in the scope of the present invention.

此外，本发明的某些化合物可以不同的互变异构体的形式存在，这些化合物能形成的任何互变异构形式均包括在本发明的范围。In addition, certain compounds of the present invention may exist in different tautomeric forms, and any tautomeric forms these compounds are capable of forming are included within the scope of the present invention.

本发明的化合物可以非溶剂化和与溶剂的溶剂化形式存在，这些溶剂例如有水、乙醇等。对于本发明的目的而言，通常认为溶剂化形式等同于非溶剂化形式。The compounds of the present invention can exist in unsolvated as well as solvated forms with solvents, such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

外消旋形式可用已知的方法拆分为旋光对映体，例如通过用光学活性酸分离形成的非对映体盐，随后通过用碱处理释放出旋光活性胺化合物。另一种将外消旋体拆分为光学旋光对映体的方法是在旋光活性基质上进行层析。本发明的外消旋化合物还可通过例如d-或l-酒石酸盐、扁桃酸盐或樟脑磺酸盐的分级结晶拆分为其旋光对映体。本发明的化合物还可通过形成非对映衍生物来拆分。The racemic forms can be resolved into the optical antipodes by known methods, for example by separation of the formed diastereomeric salts with an optically active acid, followed by treatment with a base to liberate the optically active amine compound. Another method for the resolution of racemates into optical antipodes is chromatography on optically active matrices. The racemic compounds of the invention can also be resolved into their optical antipodes by, for example, fractional crystallization of the d- or 1-tartrate, mandelate or camphorsulfonate salts. The compounds of the invention can also be resolved by the formation of diastereomeric derivatives.

可使用本领域技术人员公知的其他拆分光学异构体的方法。这些方法包括J.Jaques，A.Collet和S.Wilen在“对映异构体、外消旋体及拆分”(“Enantiomers，Racemates，and Resolutions”，John Wiley和Sons，New York，1981)中描述的那些。Other methods of resolution of optical isomers known to those skilled in the art can be used. These methods include J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York, 1981) those described in .

还可由光学活性的原料制备光学活性的化合物。Optically active compounds can also be prepared from optically active starting materials.

本发明还包括本发明化合物的前药，所述前药给药后通过新陈代谢作用而产生化学转化，成为药理活性物质。通常，这种前药为易于在体内转化为所需的式I、VII、VIII、IX、X、XI、XXXII或XXXIIII的化合物的式I、VII、VIII、IX、X、XI、XXXII或XXXIII的化合物的官能衍生物。用于选择和制备适合的前药衍生物的常规步骤例如描述于“前药设计”(“Design of Prodrugs”，H.Bundgaard编，Elsevier，1985)。The present invention also includes the prodrugs of the compounds of the present invention. After administration, the prodrugs undergo chemical transformation through metabolism to become pharmacologically active substances. Typically, such prodrugs are those of formula I, VII, VIII, IX, X, XI, XXXII or XXXIII that are readily converted in vivo to the desired compound of formula I, VII, VIII, IX, X, XI, XXXII or XXXIII. functional derivatives of compounds. Routine procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

本发明还包括本发明化合物的活性代谢物。The present invention also includes active metabolites of the compounds of the present invention.

无论何时提及与式I、VII、VIII、IX、X、XI、XXXII或XXXIII的化合物相关的术语“癫痫和各种癫痫”包括在国际抗癫痫联盟：关于修订癫痫发作的临床和脑电图分类的建议，国际抗癫痫联盟分类和技术委员会，Epilepsia，198122：489-501以及国际抗癫痫联盟：关于修订癫痫和癫痫综合征的分类的建议，国际抗癫痫联盟分类和技术委员会，Epilepsia，198930(4)：389-399中提出的任何癫痫、癫痫综合症以及癫痫发作。Whenever the term "epilepsy and various epilepsy" is referred to in relation to a compound of formula I, VII, VIII, IX, X, XI, XXXII or XXXIII is included in the International League Against Epilepsy: Clinical and EEG Proposals for Classification of Figures, International League Against Epilepsy Classification and Technical Committee, Epilepsia, 198122: 489-501 and International League Against Epilepsy: Proposals for Revision of the Classification of Epilepsy and Epilepsy Syndromes, International League Against Epilepsy Classification and Technical Committee, Epilepsia, 198930(4):389-399 any epilepsy, epileptic syndrome and seizures.

无论何时提及与式I、VII、VIII、IX、X、XI、XXXII或XXXIII化合物有关的术语焦虑症包括焦虑症包含涉及如美国精神学会精神疾病诊断与统计手册，1994第4版：110-113，393-444和623-627定义的惊恐发作、广场恐怖症、旷野恐怖性惊恐症(panic disorder withagoraphobia)、无旷野恐怖性惊恐症、无惊恐发作史的广场恐怖症、特异性恐怖症、社交恐惧症、强迫观念与行为症、创伤后应激症、急性应激反应、广泛性焦虑症、起因于全身健康状况的焦虑症、物质诱导的焦虑症、分离焦虑症、适应性障碍和未加说明的焦虑症。Whenever reference is made to the term anxiety disorder in relation to a compound of formula I, VII, VIII, IX, X, XI, XXXII or XXXIII, including anxiety disorder includes references such as the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 1994 4th Edition: 110 -113, panic attacks as defined in 393-444 and 623-627, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without history of panic attacks, specific phobia , social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress response, generalized anxiety disorder, anxiety disorder arising from a general health condition, substance-induced anxiety disorder, separation anxiety disorder, adjustment disorder, and Unspecified anxiety disorder.

                         药物组合物                        

本发明的化合物通常以游离碱或其药学上可接受的盐使用。代表性实例如上所述。The compounds of the present invention are generally employed as free bases or pharmaceutically acceptable salts thereof. Representative examples are described above.

如需要，本发明的药物组合物可包含式I化合物和其他如前所述的药理活性物质。If necessary, the pharmaceutical composition of the present invention may contain the compound of formula I and other pharmacologically active substances as mentioned above.

本发明的化合物可单独或结合药学上可接受的载体或赋形剂单剂量或多剂量给药。本发明的药用组合物可与药学上可接受的载体或稀释剂以及任何本领域常规工艺已知的其他添加剂和赋形剂调配，如Remington：The Science and Practice of Pharmacy(第19版，Gennaro编，Mack Publishing Co.，Easton，PA，1995)中公开的那些。The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or excipients in single or multiple doses. The pharmaceutical composition of the present invention can be formulated with a pharmaceutically acceptable carrier or diluent and any other additives and excipients known in the conventional art, such as Remington: The Science and Practice of Pharmacy (19th edition, Gennaro eds., Mack Publishing Co., Easton, PA, 1995).

所述药用组合物可具体调配用于经任何适合的途径给药，如口、直肠、鼻、肺、局部(包括颊和舌下)、经皮、脑池内、腹膜内、阴道和胃肠外(包括皮下、肌内、鞘内、静脉内和真皮内)途径，优选口服途径。优选的途径取决于被治疗者的全身健康状况和年龄、被治疗疾病的性质以及所选的活性组分。The pharmaceutical compositions may be specifically formulated for administration via any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and gastrointestinal External (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes, preferably oral routes. The preferred route will depend on the general health and age of the person being treated, the nature of the disease being treated and the active ingredient chosen.

口服给药的药物组合物包括固体剂型如胶囊、片剂、糖衣丸、丸剂、锭剂、散剂和颗粒剂。如有需要，可将其包衣(如肠溶包衣)或采用如本领域熟知的维持或延长释放的方法将其制成提供活性成分的控制释放的制剂。Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. If desired, they may be coated (eg, enteric coated) or formulated to provide controlled release of the active ingredient by sustained or prolonged release methods as is well known in the art.

口服给药的液体剂型包括溶液剂、乳剂、混悬剂、糖浆剂和酏剂。Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

胃肠外给药的药物组合物包括无菌水溶液和非水注射溶液、分散液、混悬剂或乳剂以及在用前重新配成无菌注射溶液或分散液的无菌粉末。长效注射制剂也在本发明考虑的范围内。Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injection solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injection solutions or dispersions before use. Depot injectable formulations are also contemplated by the present invention.

其他适合的给药形式包括栓剂、喷雾剂、油膏、乳剂、凝胶、吸入剂、皮肤贴片和植入片等。Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants, and the like.

本发明的药物组合物或根据本发明制备的药物组合物可通过任何合适的途径给药，例如以片剂、胶囊剂、散剂、糖浆剂等形式口服给药或以注射用溶液剂的形式胃肠外给药。对于制备这些组合物，可使用本领域熟知的方法和使用本领域通常使用的任何药学上可接受的载体、稀释剂、赋形剂或其他添加剂。The pharmaceutical composition of the present invention or the pharmaceutical composition prepared according to the present invention can be administered by any suitable route, such as oral administration in the form of tablet, capsule, powder, syrup, etc. or gastric administration in the form of solution for injection. Parenteral administration. For the preparation of these compositions, methods well known in the art and any pharmaceutically acceptable carriers, diluents, excipients or other additives commonly used in the art can be used.

通常口服剂量为约0.001至约100mg/kg体重/天，优选约0.01至约50mg/kg体重/天，并更优选约0.05至约10mg/kg体重/天，单或多剂量如1至3剂量给药。确切的剂量将取决于给药的方式和频率、性别、年龄、治疗对象的体重和全身健康状况、治疗病症的性质、治疗病症和任何治疗的并发症的严重性以及其他对本领域技术人员来说显而易见的因素。Usual oral dosage is about 0.001 to about 100 mg/kg body weight/day, preferably about 0.01 to about 50 mg/kg body weight/day, and more preferably about 0.05 to about 10 mg/kg body weight/day, single or multiple doses such as 1 to 3 doses medication. The exact dosage will depend on the mode and frequency of administration, sex, age, body weight and general health of the subject being treated, the nature of the condition being treated, the severity of the condition being treated and any complications of the treatment, and other factors apparent to those skilled in the art. Obvious factor.

所述制剂可方便地以由本领域技术人员已知的方法形成的单位剂量存在。用于每天一次或多次(如每天1至3次)口服给药的通常单位剂量可含0.05至约1000mg，优选约0.1至约500mg，更优选约0.5mg至约200mg。The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. Usual unit doses for oral administration one or more times per day (eg 1 to 3 times per day) may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, more preferably from about 0.5 mg to about 200 mg.

胃肠道外途径如静脉、鞘内、肌内和类似的给药途径，通常为口服给药使用剂量的约一半。Parenteral routes of administration, such as intravenous, intrathecal, intramuscular and similar routes, generally use about half the dosage for oral administration.

本发明的化合物通常作为游离的物质或其药学可接受的盐使用。一个实例为具有游离酸用途的化合物的碱加成盐。当本发明的化合物包含游离酸时，可采用常规的方法通过用化学当量的药学上可接受的碱来处理本发明的化合物的游离酸的溶液或悬浮液制备这些盐。代表性的实例如前所述。The compounds of the present invention are generally used as free substances or pharmaceutically acceptable salts thereof. An example is the base addition salt of a compound with free acid utility. When the compound of the present invention contains a free acid, these salts can be prepared by conventional methods by treating a solution or suspension of the free acid of the compound of the present invention with a chemical equivalent of a pharmaceutically acceptable base. Representative examples are as described above.

对于胃肠外给药，可使用本发明新型化合物在无菌水、含水丙二醇、含水维他命E或芝麻油或花生油中的溶液。如需要，这些含水溶液可适当缓冲并先用足够的盐或葡萄糖将液体稀释剂调节至等渗。所述含水溶液特别适合静脉、肌内、皮下和腹腔内给药。使用的无菌水介质都通过本领域的技术人员已知的标准技术容易地获得。For parenteral administration, solutions of the novel compounds of the invention in sterile water, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be used. These aqueous solutions can be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. Said aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media used are all readily obtained by standard techniques known to those skilled in the art.

可以通过下面方法制备注射用溶液：将活性成分和可行的添加剂溶解于部分注射用溶剂中，优选溶解于无菌水中，调节所述溶液至所需体积，对所述溶液进行灭菌，将其装入合适的安瓿或管瓶中。可以加入常规用于本领域的任何合适添加剂如张度剂(tonicityagents)、防腐剂、抗氧化剂等。Solutions for injection can be prepared by dissolving the active ingredient and possible additives in part of the solvent for injection, preferably in sterile water, adjusting the solution to the desired volume, sterilizing the solution, and dissolving it Fill into suitable ampoules or vials. Any suitable additives conventionally used in the art such as tonicity agents, preservatives, antioxidants, etc. may be added.

合适的药用载体包括惰性固体稀释剂或填充剂、无菌水溶液和各种有机溶剂。Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.

固体载体的实例为乳糖、白土、蔗糖、环糊精、滑石粉、琼脂、果胶、阿拉伯胶、硬脂酸和玉米淀粉纤维素的低级烷醚、马铃薯淀粉、滑石、硬脂酸镁、明胶、乳糖、树胶等。Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, agar, pectin, acacia, stearic acid and lower alkyl ethers of corn starch cellulose, potato starch, talc, magnesium stearate, gelatin , lactose, gum, etc.

可使用用于这些目的的任何其他辅料或添加剂，(如着色剂、矫味剂、防腐剂等)条件是其与活性成分相容。Any other adjuvant or additive used for these purposes (eg colourings, flavorings, preservatives etc.) may be used provided that it is compatible with the active ingredient.

液体载体的实例为糖浆、花生油、橄榄油、磷脂、脂肪酸、脂肪酸胺、聚氧乙烯和水。同样地，所述载体或稀释剂可包括任何本领域已知的缓释材料，如单硬脂酸甘油酯或二硬脂酸甘油酯(单独或与蜡混合使用)。Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Likewise, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.

然后本发明的新型化合物和药学上可接受的载体混合形成的药物组合物以适用于公开的给药途径的各种剂型容易地给药。通过药学领域已知的方法可方便地制备单元剂量的剂型。The pharmaceutical compositions formed by admixing the novel compounds of the present invention and pharmaceutically acceptable carriers are then readily administered in various dosage forms suitable for the disclosed routes of administration. The dosage unit dosage forms may conveniently be prepared by methods known in the art of pharmacy.

本发明合适的口服给药的制剂可以分散单位(如胶囊或片剂)存在，每片包含预定量的活性成分，并可包括一种或多种合适的赋形剂。此外，口服用制剂可为散剂或颗粒剂、水或非水液体中的溶液或混悬剂，或者为水包油或油包水液体乳剂。Suitable formulations of the invention for oral administration may be presented as discrete units such as capsules or tablets, each tablet containing a predetermined amount of the active ingredient, and which may include one or more suitable excipients. Additionally, formulations for oral administration may be powders or granules, solutions or suspensions in water or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions.

假如将固体载体用于口服给药，所述制剂可为以粉末或小丸的形式置于硬明胶胶囊中的片剂或其可为锭剂。If a solid carrier is used for oral administration, the preparation may be a tablet placed in a hard gelatine capsule in powder or pellet form or it may be a lozenge.

固体载体量的范围很宽，但通常为约25mg至约1g。The amount of solid carrier can vary widely but will usually be from about 25 mg to about 1 g.

假如使用液体载体，所述制剂可为糖浆、乳剂、软明胶胶囊或无菌注射用液体如含水或无水的液体混悬剂或溶液。If a liquid carrier is used, the preparation may be a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or anhydrous liquid suspension or solution.

如需要，本发明的药物组合物可包括式I、VII、VIII、IX、X或XI化合物和如前所述的其他药理活性物质。If desired, the pharmaceutical composition of the present invention may comprise a compound of formula I, VII, VIII, IX, X or XI and other pharmacologically active substances as previously described.

本发明的制剂配方的典型实例如下：A typical example of the formulation of the present invention is as follows:

1)含5.0mg本发明的化合物(以游离碱计算)的片剂：1) Tablets containing 5.0 mg of the compound of the present invention (calculated as free base):

式I、VII、VIII、IX、X或XI化合物              5.0mgCompound of formula I, VII, VIII, IX, X or XI 5.0mg

乳糖                                         60mgLactose 60mg

玉米淀粉                                     30mgcornstarch 30mg

羟丙基纤维素                                 2.4mgHydroxypropyl Cellulose 2.4mg

微晶纤维素                                   19.2mgMicrocrystalline Cellulose 19.2mg

A型交联羧甲基纤维素钠                        2.4mgCroscarmellose sodium type A 2.4mg

硬脂酸镁                                     0.84mgMagnesium stearate 0.84mg

2)含5.0mg本发明的化合物(以游离碱计算)的片剂：2) Tablets containing 5.0 mg of the compound of the present invention (calculated as free base):

式I、VII、VIII、IX、X或XI化合物                    5.0mgCompound of formula I, VII, VIII, IX, X or XI 5.0 mg

乳糖                                               46.9mgLactose 46.9mg

玉米淀粉                                           23.5mgCorn Starch 23.5mg

聚维酮                                             1.8mgPovidone 1.8mg

微晶纤维素                                         14.4mgMicrocrystalline Cellulose 14.4mg

A型交联羧甲基纤维素钠                              1.8mgCroscarmellose sodium type A 1.8mg

硬脂酸镁                                           0.63mgMagnesium stearate 0.63mg

3)每毫升糖浆含：3) Each milliliter of syrup contains:

式I、VII、VIII、IX、X或XI的化合物                  25mgCompound of formula I, VII, VIII, IX, X or XI 25 mg

山梨醇                                             500mgSorbitol 500mg

羟丙基纤维素                                       15mgHydroxypropyl Cellulose 15mg

甘油                                               50mgGlycerin 50mg

对羟基苯甲酸甲酯                                   1mgMethylparaben 1mg

对羟基苯甲酸丙酯                                   0.1mgPropylparaben 0.1mg

乙醇                                               0.005mgEthanol 0.005mg

香精                                               0.05mgFragrance 0.05mg

糖精钠                                             0.5mgSodium saccharin 0.5mg

水                                                 加至1mlAdd water to 1ml

4)每毫升注射用溶液含：4) Each milliliter of solution for injection contains:

式I、VII、VIII、IX、X或XI的化合物                  0.5mgCompound of formula I, VII, VIII, IX, X or XI 0.5 mg

山梨醇                                             5.1mgSorbitol 5.1mg

乙酸                                               0.05mgAcetic acid 0.05mg

糖精钠                                             0.5mgSodium saccharin 0.5mg

水                                                 加至1mlAdd water to 1ml

                  本发明的化合物的制备Preparation of the compound of the present invention

方案1plan 1

方案2Scenario 2

Figure A20048001101900812
Figure A20048001101900812

通式I的本发明的化合物(其中虚线、q、s、U、Y、X、Z、R1、R1’、R2和R3如上定义，因此任何虚线、a、b、c、d、e、f、g、h、s、q、U、X、Z、Y、W、R1、R1’、R2、R3、R5、R6、R6’、R7、R7’、R8、R9、R9’、R10、R10’、R11、R12和R12’如式I定义)如方案1和方案2所示按如下所述方法制备。Compounds of the invention of general formula I (wherein dashed lines, q, s, U, Y, X, Z, R 1 , R 1′ , R 2 and R 3 are as defined above, so any dashed lines, a, b, c, d , e, f, g, h, s, q, U, X, Z, Y, W, R 1 , R 1' , R 2 , R 3 , R 5 , R 6 , R 6' , R 7 , R 7' , R 8 , R 9 , R 9' , R 10 , R 10' , R 11 , R 12 and R 12' are as defined in Formula I) as shown in Scheme 1 and Scheme 2 and prepared as follows.

在4位或6位被R2-(U)s-取代的通式XII和XIII的吲哚和二氢吲哚可市售得到，在文献中已有描述或根据本领域化学技术人员已知的方法制备[R.J.Sundberg“Pyrroles and their Benzo Derivatives：(iii)Synthesis and Applications(吡咯及其苯并衍生物：(iii)合成和应用)”，Comprehensive Heterocyclic Chemistry，A.R.Katritzky，C.W.Rees(编辑)，第IV卷，第313-376页，Pergamon Press，1984]。通过本领域化学技术人员已知的方法如催化氢化或在合适的溶剂(如乙酸)中使用NaBH3CN还原[S.M.Bromidge，S.Dabbs，D.T.Davies，D.M.Duckworth，I.T.Forbes等J.Med.Chem.41，1998，1598-1612]，可将通式XII的吲哚转化为通式XIII的二氢吲哚。通过本领域化学技术人员已知的C-C偶联反应(如Suzuki偶联、Stille偶联或其他过渡金属催化的交联反应[D.W.Knight“Coupling Reactions Between sp2 Carbon Centers(sp2碳中心之间的偶联反应)”，Comprehensive Organic Synthesis，第3卷，第481-520页，Pergamon Press 1991]，s为0且R2具体为但不限于如上定义的取代的芳基或取代的杂芳基的通式XII或XIII的化合物可由R2为I或Br的相应的化合物制备。Indoles and indolines of the general formula XII and XIII substituted by R 2 -(U) s - in the 4- or 6-position are commercially available, described in the literature or known to those skilled in the art [RJSundberg "Pyrroles and their Benzo Derivatives: (iii) Synthesis and Applications (pyrroles and their benzo derivatives: (iii) synthesis and application)", Comprehensive Heterocyclic Chemistry, ARKatritzky, CWRees (editor), Vol. IV , pp. 313-376, Pergamon Press, 1984]. By methods known to chemists skilled in the art such as catalytic hydrogenation or reduction using NaBH CN in a suitable solvent such as acetic acid [SM Bromidge, S. Dabbs, DT Davies, DMDuckworth, IT Forbes et al. J. Med. Chem. 41, 1998, 1598 -1612], the indole of general formula XII can be converted into the indoline of general formula XIII. Through CC coupling reactions known to those skilled in the art (such as Suzuki coupling, Stille coupling, or other transition metal-catalyzed cross-linking reactions [DWKnight "Coupling Reactions Between sp2 Carbon Centers (Coupling reactions between sp2 carbon centers) )", Comprehensive Organic Synthesis, Volume 3, pages 481-520, Pergamon Press 1991], s is 0 and R is specifically, but not limited to, the general formula XII of substituted aryl or substituted heteroaryl as defined above or XIII compounds can be prepared from the corresponding compounds where R is I or Br.

通过在合适的温度下、合适的溶剂(如1，2-二氯乙烷)中与试剂(如三氟乙酸酐)反应形成合适的保护基团(PG1)[Protective Groups inOrganic Synthesis(有机合成中的保护基团)，第三版T.W.Greene，P.G.M.Wuts，Wiley Interscience 1999]，如三氟乙酰基(即本领域化学技术人员已知的TFA基)保护基团来保护通式XIII的化合物二氢吲哚的氮，制备通式XIV的化合物。A suitable protecting group (PG 1 ) is formed by reaction with a reagent such as trifluoroacetic anhydride in a suitable solvent such as 1,2-dichloroethane at a suitable temperature [Protective Groups in Organic Synthesis Protecting group in), third edition TWGreene, PGM Wuts, Wiley Interscience 1999], such as trifluoroacetyl (ie TFA group known to those skilled in the art) protecting group to protect the compound indoline of general formula XIII The nitrogen of the indole to prepare compounds of general formula XIV.

通过本领域化学技术人员已知的方法[R.Behnisch“AromatischeNitro-Verbindungen”，Methoden der Organische Chemiel，Houben-Weyl，第255页，v.E16d，Thieme：1992]如在合适的温度下、合适的溶剂(如乙酸酐、乙酸、浓硫酸或其混合物)中与浓硝酸反应，区域选择性硝化二氢吲哚部分的5位，这样将得到的通式XIV的化合物转化为通式XV的化合物。通过本领域化学技术人员已知的亲核芳族的取代反应，例如与形成-(U)s-R2基团的合适的亲核试剂(如中性或去质子化形式的苯硫酚、烷基硫化物、醇、苯酚、胺和苯胺)反应，通式XV的硝基化合物(其中R2为卤素、尤其为氟且s为0)可转化为通式XV的化合物(其中U为O、NR11或S且R2如上定义)。通过本领域化学技术人员已知的氧化方法，例如用催化剂RuCl3存在下的NaIO4氧化或用3-氯过苯甲酸氧化，可由通式XV的化合物(其中U为S)得到通式XV化合物(其中U为SO2)。By methods known to chemists skilled in the art [R. Behnisch "Aromatische Nitro-Verbindungen", Methoden der Organische Chemiel, Houben-Weyl, p. 255, v. E16d, Thieme: 1992] such as at a suitable temperature, a suitable Reaction with concentrated nitric acid in a solvent (such as acetic anhydride, acetic acid, concentrated sulfuric acid or mixtures thereof) regioselectively nitrates the 5-position of the indoline moiety, thus converting the resulting compound of formula XIV into a compound of formula XV. By nucleophilic aromatic substitution reactions known to those skilled in the art, for example with a suitable nucleophile forming a -(U) s - R group (such as thiophenol in neutral or deprotonated form, Alkyl sulfides, alcohols, phenols, amines and anilines) reactions, nitro compounds of general formula XV (wherein R 2 is halogen, especially fluorine and s is 0) can be converted into compounds of general formula XV (wherein U is O , NR 11 or S and R 2 as defined above). Compounds of general formula XV, wherein U is S, can be obtained from compounds of general formula XV by oxidation methods known to those skilled in the art, such as oxidation with NaIO in the presence of catalyst RuCl or oxidation with 3 -chloroperbenzoic acid (wherein U is SO2 ).

在合适的温度或超声处理下、合适的溶剂(如甲醇、乙醇或四氢呋喃)中、合适的氢化催化剂(如钯碳)存在下、在酸(如乙酸或盐酸)、氢气或甲酸铵的存在下可使用合适的还原剂(如锌或铁粉)，将通式XV的化合物中的硝基还原，得到通式XVI的苯胺。或者，在本领域化学技术人员熟知的条件下可使用二氯化锡或连二硫酸钠作为还原剂。At a suitable temperature or sonication, in a suitable solvent such as methanol, ethanol or tetrahydrofuran, in the presence of a suitable hydrogenation catalyst such as palladium on carbon, in the presence of an acid such as acetic acid or hydrochloric acid, hydrogen gas or ammonium formate The nitro group in the compound of general formula XV can be reduced using a suitable reducing agent such as zinc or iron powder to give the aniline of general formula XVI. Alternatively, tin dichloride or sodium dithionate can be used as reducing agent under conditions well known to those skilled in the art.

在合适的温度(如室温或回流温度)下、合适的溶剂(如乙腈、四氢呋喃、1，2-二氯乙烷或二氯甲烷)中、加或不加碱(如氧化镁、碳酸钾、氢化钠、三烷基胺、醇钠或醇钾或吡啶)，通过与合适的形成R3-(Z)q-X基团的亲电试剂(如氯甲酸烷基酯、氯甲酸芳基酯或氯甲酸杂芳酯或氨基甲酰氯、酰氯、酰溴、酰碘、磺酰氯、异氰酸酯、碳酸酐、用活化剂如碳二亚胺或其他本领域化学技术人员已知的活化剂活化的碳酸)反应，由通式XVI的化合物制备通式XVII的化合物，反应为本领域化学技术人员公知。然后根据本领域化学技术人员已知的方法移去保护基团PG1[Protective Groups in Organic Synthesis(有机合成中的保护基团)，第三版，T.W.Greene，P.G.M.Wuts，WileyInterscience 1999]，得到通式XVIII的化合物。例如当PG1为TFA时，可在合适的温度下、合适的溶剂(如甲醇)中用碳酸钾水溶液水解移去该基团。At a suitable temperature (such as room temperature or reflux temperature), in a suitable solvent (such as acetonitrile, tetrahydrofuran, 1,2-dichloroethane or dichloromethane), with or without adding a base (such as magnesium oxide, potassium carbonate, sodium hydride, trialkylamine, sodium or potassium alkoxide or pyridine), by reacting with a suitable electrophile forming the R 3 -(Z) q -X group (such as alkyl chloroformate, aryl chloroformate or heteroaryl chloroformate or carbamoyl chloride, acid chloride, acid bromide, acid iodide, sulfuryl chloride, isocyanate, carbonic anhydride, carbonic acid activated with an activator such as carbodiimide or other activators known to those skilled in the art ) reaction, the compound of general formula XVII is prepared from the compound of general formula XVI, and the reaction is well known to those skilled in the art. The protecting group PG 1 is then removed according to methods known to chemists skilled in the art [Protective Groups in Organic Synthesis (protecting groups in organic synthesis), third edition, TW Greene, PGM Wuts, Wiley Interscience 1999], resulting in general formula XVIII compound of. For example, when PG 1 is TFA, the group can be removed by hydrolysis with potassium carbonate aqueous solution at a suitable temperature in a suitable solvent (such as methanol).

最后，在合适的温度下、合适的溶剂(如甲醇、乙醇、四氢呋喃、乙腈或其混合物)中、合适的还原剂(如NaBH3CN)的存在下、加或不加催化剂量的酸(如乙酸)，通过本领域化学技术人员已知的还原烷基化反应将得到的通式XVIII的苯胺与通式YCHO的醛(其中Y如上定义)反应，形成通式I的本发明的化合物(其中R1和R1’为氢)。或者，在本领域化学技术人员已知的条件下，通过与通式(Y)(R1)(R1’)C-LG的合适的亲电试剂(其中LG为合适的离去基团，如碘、溴或磺酸根(sulphonate))的亲核取代反应引入(Y)(R1)(R1’)C-基团，得到通式I的本发明的化合物。Finally, at a suitable temperature, in a suitable solvent (such as methanol, ethanol, tetrahydrofuran, acetonitrile, or mixtures thereof), in the presence of a suitable reducing agent (such as NaBHCN ), with or without the addition of a catalytic amount of an acid (such as acetic acid), the resulting aniline of general formula XVIII is reacted with an aldehyde of general formula YCHO (wherein Y is as defined above) by a reductive alkylation reaction known to those skilled in the art to form compounds of the invention of general formula I (wherein R and R are hydrogen). Alternatively, by reacting with a suitable electrophile of general formula (Y)(R 1 )(R 1′ )C-LG (wherein LG is a suitable leaving group, Nucleophilic substitution reactions such as iodine, bromine or sulphonate) introduce (Y)(R 1 )(R 1′ )C-groups to give compounds of the invention of general formula I.

或者，通式XIX的化合物为市售、按照文献所述或可由通式XV的化合物通过如上所述去保护制备。然后将其与通式YCHO的醛发生还原烷基化或与如上所述的通式(Y)(R1)(R1’)C-LG的亲电试剂发生亲核取代反应，得到通式XX的化合物。然后如前所述将硝基还原，形成通式XXI的化合物。最终，通过上述将通式XVI的化合物转化为通式XVII的化合物的方法，得到具有二氢吲哚部分的通式I的本发明的化合物。Alternatively, compounds of general formula XIX are commercially available, described in the literature or can be prepared from compounds of general formula XV by deprotection as described above. This is then subjected to reductive alkylation with an aldehyde of the general formula YCHO or a nucleophilic substitution reaction with an electrophile of the general formula (Y)(R 1 )(R 1' )C-LG as described above to give the general formula Compound of XX. The nitro group is then reduced as previously described to form compounds of general formula XXI. Finally, the compound of the invention of formula I having an indoline moiety is obtained by the above-mentioned method of converting a compound of formula XVI into a compound of formula XVII.

任选在合适的温度下、合适的溶剂(如甲苯或二甲苯)中，通过本领域化学技术人员已知的脱氢作用，如使用合适的试剂(如2，3，5，6-四氯-[1，4]苯醌、MnO2)氧化或在催化剂(如钯碳或RuCl2(PPh3)3)的存在下催化脱氢，可由通式I的二氢吲哚得到具有吲哚部分的通式I的本发明的化合物。Optionally at a suitable temperature, in a suitable solvent such as toluene or xylene, by dehydrogenation known to those skilled in the art, such as using a suitable reagent such as 2,3,5,6-tetrachloro -[1,4]benzoquinone, MnO 2 ) oxidation or catalytic dehydrogenation in the presence of a catalyst (such as palladium on carbon or RuCl 2 (PPh 3 ) 3 ), can be obtained from indolines of general formula I with indole moieties Compounds of the invention of the general formula I.

或者，通式I化合物(其中-(U)s-R2连接在二氢吲哚部分的6位)可按照方案2中所示的路线如下制备：Alternatively, compounds of general formula I (wherein -(U) s -R 2 is attached to the 6-position of the indoline moiety) can be prepared according to the route shown in Scheme 2 as follows:

采用与上述通式XIV的化合物相同的方法，用合适的保护基团(如TFA基)保护5-硝基二氢吲哚，得到通式XXII的化合物。然后采用上述制备通式XVI的化合物的方法将硝基还原，得到通式XXIII的化合物。然后采用上述制备通式XVII的化合物的方法，使用合适的形成R3-(Z)q-X的亲电试剂，将其转化为通式XXIV的化合物。通过在合适的溶剂(如乙酸)中与合适的亲电试剂(如N-氯琥珀酰亚胺、溴、碘、氯化碘(iodochloride))经本领域化学技术人员熟知的区域选择性亲电芳族取代，或者采用制备通式XV的化合物的条件硝化，得到通式XXV的化合物(其中s为0，且R2为NO2或卤原子如Cl、Br或I)。Using the same method as the compound of general formula XIV above, 5-nitroindoline is protected with a suitable protecting group (such as TFA group) to obtain a compound of general formula XXII. The nitro group is then reduced using the methods described above for the preparation of compounds of general formula XVI to obtain compounds of general formula XXIII. This is then converted to a compound of general formula XXIV using the appropriate R3- (Z) q -X forming electrophile using the methods described above for the preparation of compounds of general formula XVII. By reaction with a suitable electrophile (such as N-chlorosuccinimide, bromine, iodine, iodochloride) in a suitable solvent (such as acetic acid) by regioselective electrophile well known to those skilled in the art Aromatic substitution, or nitration using the conditions used to prepare compounds of general formula XV, yields compounds of general formula XXV (wherein s is 0 and R2 is NO2 or a halogen atom such as Cl, Br or I).

通式XXV的化合物(其中s为0，且R2为如上定义的取代的芳基或取代的杂芳基)可由相同通式的相应的化合物(其中R2为I或Br)经如上所述的本领域化学技术人员已知的C-C偶联反应制备。然后如上所述移去保护基团，得到通式XXVI的化合物。Compounds of general formula XXV (wherein s is 0 and R is a substituted aryl or substituted heteroaryl as defined above) can be prepared from corresponding compounds of the same general formula (wherein R is I or Br) by prepared by CC coupling reactions known to those skilled in the art. The protecting group is then removed as described above to afford compounds of general formula XXVI.

最终，由通式XXVI的化合物通过如上所述的还原烷基化或亲核取代反应制备具有二氢吲哚部分的通式I的本发明的化合物。同样由通式I的二氢吲哚通过如上所述脱氢作用可得到具有吲哚部分的通式I的本发明的化合物。Finally, compounds of the invention of formula I having an indoline moiety are prepared from compounds of formula XXVI by reductive alkylation or nucleophilic substitution reactions as described above. Compounds of the invention having the indole moiety are likewise obtainable from indolines of the formula I by dehydrogenation as described above.

                         实施例Example

LC-MS分析数据得自装有APPI(常压光致电离)离子源和Shimadzu LC-8A/SLC-10A LC系统的PE Sciex API 150EX仪器。柱：30×4.6mm Waters Symmetry C18柱，填料粒径为3.5μm；溶剂体系：A＝水/三氟乙酸(100∶0.05)，B＝水/乙腈/三氟乙酸(5∶95∶0.03)；方法：在4分钟内以2ml/min的流速用90％A-100％B线性梯度洗脱。用UV(254nm)和ELSD迹线的积分确定纯度。保留时间(RT)以分钟计。LC-MS analysis data were obtained from PE Sciex API 150EX instrument equipped with APPI (atmospheric pressure photoionization) ion source and Shimadzu LC-8A/SLC-10A LC system. Column: 30×4.6mm Waters Symmetry C18 column, the packing particle size is 3.5μm; solvent system: A=water/trifluoroacetic acid (100:0.05), B=water/acetonitrile/trifluoroacetic acid (5:95:0.03) ; Method: eluted with a linear gradient of 90% A-100% B in 4 minutes at a flow rate of 2 ml/min. Purity was determined by integration of UV (254 nm) and ELSD traces. Retention times (RT) are in minutes.

在相同的仪器上进行制备型LC-MS纯化。柱：50×20mm YMCODS-A柱，填料粒径为5μm；方法：在7分钟内以22.7ml/min的流速用80％A-100％B线性梯度洗脱。通过分流MS检测收集馏分。Preparative LC-MS purification was performed on the same instrument. Column: 50×20mm YMCODS-A column, the packing particle size is 5μm; method: 80%A-100%B linear gradient elution at a flow rate of 22.7ml/min within 7 minutes. Fractions were collected by split flow MS detection.

在Bruker Avance DRX500仪器、500.13MHz下记录1H NMR波谱。使用氘代氯仿(99.8％D)或二甲亚砜(99.8％D)作为溶剂。用TMS作为内标。化学位移值以ppm值表示。使用下述缩写表示多种NMR信号：s＝单峰，d＝双重峰，t＝三重峰，q＝四重峰，qui＝五重峰，h＝七重峰，dd＝双重双峰，dt＝双重三峰，dq＝双重四峰，tt＝三重三峰，m＝多重峰，br.＝宽峰。 1 H NMR spectra were recorded on a Bruker Avance DRX500 instrument, 500.13 MHz. Deuterochloroform (99.8%D) or dimethylsulfoxide (99.8%D) was used as solvent. TMS was used as internal standard. Chemical shift values are expressed in ppm. The following abbreviations are used to denote various NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = septet, dd = doublet of doublets, dt = Double triplet, dq = double quadruplet, tt = triplet triplet, m = multiplet, br. = broad.

                         中间体的制备Preparation of intermediates

                   通式XXII和XIV中间体的制备Preparation of intermediates of general formula XXII and XIV

1-三氟乙酰基-5-硝基二氢吲哚1-Trifluoroacetyl-5-nitroindoline

往5-硝基二氢吲哚(5.51g，33.56mmol)在1，2-二氯乙烷(15ml)中的悬浮液中加入三氟乙酸酐(20ml)。60分钟后用庚烷(200ml)将得到的溶液猝灭，分两批(two crops)过滤分离标题化合物，得到7.12g，收率为81.5％。1H NMR(DMSO-d6)：3.34(t，2H)，4.38(t，2H)，8.19(m，3H)。To a suspension of 5-nitroindoline (5.51 g, 33.56 mmol) in 1,2-dichloroethane (15 mL) was added trifluoroacetic anhydride (20 mL). After 60 minutes the resulting solution was quenched with heptane (200ml) and the title compound was isolated by filtration in two crops to give 7.12g, 81.5% yield. 1 H NMR (DMSO-d 6 ): 3.34 (t, 2H), 4.38 (t, 2H), 8.19 (m, 3H).

1-三氟乙酰基-4-氯二氢吲哚1-Trifluoroacetyl-4-chloroindoline

类似地由4-氯二氢吲哚制备[S.M.Bromidge，S.Dabbs，D.T.Davies，D.M.Duckworth，I.T.Forbes等.J.Med.Chem.41，1998，1598-1612]。1H NMR(DMSO-d6)：3.26(t，2H)，4.34(t，2H)，7.27(d，1H)，7.34(t，1H)，8.01(d，1H)。Prepared analogously from 4-chloroindoline [SM Bromidge, S. Dabbs, DT Davies, DMDuckworth, IT Forbes et al. J. Med. Chem. 41, 1998, 1598-1612]. 1 H NMR (DMSO-d 6 ): 3.26 (t, 2H), 4.34 (t, 2H), 7.27 (d, 1H), 7.34 (t, 1H), 8.01 (d, 1H).

                         通式XV中间体的制备Preparation of intermediates of general formula XV

1-三氟乙酰基-4-氯-5-硝基二氢吲哚1-Trifluoroacetyl-4-chloro-5-nitroindoline

在5小时内少量分次往1-三氟乙酰基-4-氯二氢吲哚(197mg，0.838mmol)在乙酸酐(3ml)和乙酸(0.3ml)中的溶液中加入发烟HNO3溶液(0.4ml)。将得到的反应混合物倾入冰中，用饱和的NaHCO3水溶液中和，并用乙酸乙酯萃取。经SiO2(10g)柱塞过滤该有机溶液，真空蒸发并通过硅胶快速层析纯化，用庚烷-乙酸乙酯/庚烷(1∶4)梯度洗脱，得到黄色固体状的标题化合物70mg，收率为31％。To a solution of 1-trifluoroacetyl-4-chloroindoline (197mg, 0.838mmol) in acetic anhydride (3ml) and acetic acid (0.3ml) was added fuming HNO3 solution in small portions over 5 hours (0.4ml). The resulting reaction mixture was poured into ice, neutralized with saturated aqueous NaHCO 3 , and extracted with ethyl acetate. The organic solution was filtered through a plug of SiO2 (10 g), evaporated in vacuo and purified by flash chromatography on silica gel eluting with a gradient of heptane-ethyl acetate/heptane (1:4) to give 70 mg of the title compound as a yellow solid , the yield was 31%.

1H NMR(DMSO-d6)：3.33(t，2H)，4.42(t，2H)，8.10(s，2H)。 1 H NMR (DMSO-d 6 ): 3.33 (t, 2H), 4.42 (t, 2H), 8.10 (s, 2H).

                         通式XX中间体的制备Preparation of intermediates of general formula XX

1-(5-氯噻吩-2-基甲基)-5-硝基二氢吲哚1-(5-Chlorothiophen-2-ylmethyl)-5-nitroindoline

在10分钟内往在甲醇(45ml)和乙酸(8ml)中的5-硝基二氢吲哚(3.23g，19.67mmol)和5-氯噻吩-2-甲醛(4.2g，28.6mmol)的溶液中滴加NaBH3CN(0.9g)的甲醇(8ml)溶液。将得到的反应混合物搅拌过夜。通过过滤，甲醇和水洗涤并真空干燥分离，最终得到红色结晶固体状标题化合物4.6g，收率为79.3％。LC/MS(m/z)293.9([M]+)；RT＝3.59，(UV，ELSD)98％，99.8％1H NMR(DMSO-d6)：3.04(t，2H)，3.62(t，2H)，4.68(s，2H)，6.72(d，1H)，6.98(d，1H)，7.01(d，1H)，7.85(未解析m，1H)，8.00(dd，1H)。To a solution of 5-nitroindoline (3.23g, 19.67mmol) and 5-chlorothiophene-2-carbaldehyde (4.2g, 28.6mmol) in methanol (45ml) and acetic acid (8ml) over 10 minutes A solution of NaBH 3 CN (0.9 g) in methanol (8 ml) was added dropwise. The resulting reaction mixture was stirred overnight. After separation by filtration, washing with methanol and water and vacuum drying, 4.6 g of the title compound was finally obtained as a red crystalline solid with a yield of 79.3%. LC/MS (m/z) 293.9 ([M] + ); RT = 3.59, (UV, ELSD) 98%, 99.8% 1 H NMR (DMSO-d 6 ): 3.04 (t, 2H), 3.62 (t , 2H), 4.68 (s, 2H), 6.72 (d, 1H), 6.98 (d, 1H), 7.01 (d, 1H), 7.85 (unresolved m, 1H), 8.00 (dd, 1H).

类似地使用合适的醛制备如下化合物：The following compounds were prepared similarly using the appropriate aldehyde:

1-(4-氟苄基)-5-硝基二氢吲哚1-(4-Fluorobenzyl)-5-nitroindoline

得到黄色针状物3.66g，收率为72.2％。LC/MS(m/z)272.0([M]+)；RT＝3.35，(UV，ELSD)99％，100％。1H NMR(DMSO-d6)：3.06(t，2H)，3.61(t，2H)，4.52(s，2H)，6.63(d，1H)，7.18(m，2H)，7.35(m，2H)，7.83(未解析m，1H)，7.97(dd，1H)。3.66 g of yellow needles were obtained with a yield of 72.2%. LC/MS (m/z) 272.0 ([M] + ); RT = 3.35, (UV, ELSD) 99%, 100%. 1 H NMR (DMSO-d 6 ): 3.06(t, 2H), 3.61(t, 2H), 4.52(s, 2H), 6.63(d, 1H), 7.18(m, 2H), 7.35(m, 2H ), 7.83 (unresolved m, 1H), 7.97 (dd, 1H).

                    通式XXI、XXII和XVI中间体的制备Preparation of intermediates of general formula XXI, XXII and XVI

1-(5-氯噻酚-2-基甲基)-5-氨基二氢吲哚1-(5-Chlorothiophen-2-ylmethyl)-5-aminoindoline

往冷(冰/水浴)的强烈搅拌的在THF(100ml)和乙酸(15ml)中的1-(5-氯噻吩-2-基甲基)-5-硝基二氢吲哚(4.013g，13.62mmol)溶液中少量分次加入锌粉(25g)，保持温度低于40℃。移去低温浴并在室温下继续搅拌直到反应完成(1小时)。将得到悬浮液经SiO2(25g)柱塞过滤，使用乙酸乙酯作为洗脱液。并将得到的溶液真空蒸发。将得到的残留物用饱和的NaHCO3水溶液处理，用乙酸乙酯萃取，经Na2SO4干燥并真空蒸发，得到深绿色油状标题化合物3.30g，收率为91.5％。To cold (ice/water bath) vigorously stirred 1-(5-chlorothien-2-ylmethyl)-5-nitroindoline (4.013g, 13.62mmol) solution, a small amount of gradation was added zinc powder (25g), keeping the temperature below 40°C. The cold bath was removed and stirring was continued at room temperature until the reaction was complete (1 hour). The resulting suspension was filtered through a plug of SiO2 (25 g) using ethyl acetate as eluent. And the resulting solution was evaporated in vacuo. The resulting residue was treated with saturated aqueous NaHCO 3 , extracted with ethyl acetate, dried over Na 2 SO 4 and evaporated in vacuo to afford the title compound as a dark green oil, 3.30 g, yield 91.5%.

LC/MS(m/z)265.9([M+1]+)；RT＝1.85，(UV，ELSD)93％，100％。1HNMR (DMSO-d6)：2.73(t，2H)，3.08(t，2H)，4.25(s，2H)，4.40(br.s，2H，NH2)，6.30(dd，1H)，6.41(d，1H)，6.43(未解析m，1H)，6.89(d，1H)，6.95(d，1H)。LC/MS (m/z) 265.9 ([M+1] + ); RT = 1.85, (UV, ELSD) 93%, 100%. 1 HNMR (DMSO-d 6 ): 2.73(t, 2H), 3.08(t, 2H), 4.25(s, 2H), 4.40(br.s, 2H, NH 2 ), 6.30(dd, 1H), 6.41 (d, 1H), 6.43 (unresolved m, 1H), 6.89 (d, 1H), 6.95 (d, 1H).

类似地制备如下化合物：The following compounds were prepared analogously:

1-(4-氟苄基)-5-氨基二氢吲哚1-(4-Fluorobenzyl)-5-aminoindoline

将经SiO2过滤后得到的粗产物溶解在少量的甲醇中，用饱和NaHCO3水溶液急冷，经过滤，水洗并真空干燥分离，得到深紫色固体状的标题化合物2.40g，收率为93.2％。The crude product obtained after SiO2 filtration was dissolved in a small amount of methanol, quenched with saturated NaHCO3 aqueous solution, filtered, washed with water and dried in vacuo to obtain 2.40 g of the title compound as a dark purple solid with a yield of 93.2%.

LC/MS(m/z)265.9([M+1]+)；RT＝1.74，(UV，ELSD)87％，98％.1H NMR(DMSO-d6)：2.72(t，2H)，3.01(t，2H)，4.04(s，2H)，4.36(br.s，2H，NH2)，6.28(d，1H)，6.34(d，1H)，6.44(s，1H)，7.14(t，2H)，7.38(t，2H).LC/MS (m/z) 265.9 ([M+1] + ); RT=1.74, (UV, ELSD) 87%, 98%. 1 H NMR (DMSO-d 6 ): 2.72 (t, 2H), 3.01(t, 2H), 4.04(s, 2H), 4.36(br.s, 2H, NH 2 ), 6.28(d, 1H), 6.34(d, 1H), 6.44(s, 1H), 7.14(t , 2H), 7.38(t, 2H).

1-三氟乙酰基-5-氨基二氢吲哚1-Trifluoroacetyl-5-aminoindoline

由1-三氟乙酰基-5-硝基二氢吲哚(6.67g，25.65mmol)制备标题化合物。经SiO2过滤后的粗产物不需纯化用于下一步骤。得到标题化合物6.11g，收率为100％。The title compound was prepared from 1-trifluoroacetyl-5-nitroindoline (6.67 g, 25.65 mmol). The crude product filtered through SiO2 was used in the next step without purification. 6.11 g of the title compound was obtained with a yield of 100%.

LC/MS(m/z)230.1([M]+)；RT＝1.29，(UV，ELSD)97％，98％.1H NMR(DMSO-d6)：3.10(t，2H)，4.18(t，2H)，5.18(br.s，2H，NH2)，6.43(dd，1H)，6.53(s，1H)，7.75(d，1H).LC/MS (m/z) 230.1 ([M] + ); RT = 1.29, (UV, ELSD) 97%, 98%. 1 H NMR (DMSO-d 6 ): 3.10 (t, 2H), 4.18 ( t, 2H), 5.18 (br.s, 2H, NH 2 ), 6.43 (dd, 1H), 6.53 (s, 1H), 7.75 (d, 1H).

1-三氟乙酰基-4-氯-5-氨基二氢吲哚1-Trifluoroacetyl-4-chloro-5-aminoindoline

1H NMR(CDCl3)：3.23(t，2H)，4.28(t，2H)，6.67(d，1H)，7.93(d，1H). 1 H NMR (CDCl 3 ): 3.23(t, 2H), 4.28(t, 2H), 6.67(d, 1H), 7.93(d, 1H).

                    通式XXIV和XVII中间体的制备Preparation of intermediates of general formula XXIV and XVII

3，3-二甲基-N-[1-(2，2，2-三氟乙酰基)-2，3-二氢-1H-吲哚-5-基]-丁酰3,3-Dimethyl-N-[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]-butyryl 胺amine

往冷(冰/水浴)的1-三氟乙酰基-5-氨基二氢吲哚(2.69g，11.7mmol)的CH2Cl2溶液中加入叔丁基乙酰氯(1.88g，14mmol)，随后加入Et3N(4ml)。5分钟后用饱和NaHCO3水溶液将该反应混合物猝灭并搅拌30分钟。有机层经SiO2(20g)柱塞过滤，用乙酸乙酯作为洗脱液并蒸发至少量体积。使用庚烷急冷，经过滤分离得到白色固体状标题化合物3.10g，收率为81％。To a cold (ice/water bath) solution of 1-trifluoroacetyl-5-aminoindoline ( 2.69 g, 11.7 mmol) in CH2Cl2 was added tert-butylacetyl chloride (1.88 g, 14 mmol), followed by Et3N (4ml) was added. After 5 minutes the reaction mixture was quenched with saturated aqueous NaHCO 3 and stirred for 30 minutes. The organic layer was filtered through a plug of SiO2 (20 g) using ethyl acetate as eluent and evaporated to a small volume. It was quenched with heptane and separated by filtration to obtain 3.10 g of the title compound as a white solid with a yield of 81%.

LC/MS(m/z)329.2([M+1]+)；RT＝3.04，(UV，ELSD)97％，100％.1H MR(DMSO-d6)：1.02(s，9H)，2.18(s，2H)，3.22(t，2H)，4.26(t，2H)，7.38(dd，1H)，7.72(s，1H)，7.96(d，1H)，9.86(s，1H，NHCO).LC/MS (m/z) 329.2 ([M+1] + ); RT=3.04, (UV, ELSD) 97%, 100%. 1 H MR (DMSO-d 6 ): 1.02 (s, 9H), 2.18(s, 2H), 3.22(t, 2H), 4.26(t, 2H), 7.38(dd, 1H), 7.72(s, 1H), 7.96(d, 1H), 9.86(s, 1H, NHCO) .

类似地由1-三氟乙酰基-5-氨基二氢吲哚和合适的酰氯或氯甲酸酯制备如下化合物：The following compounds were prepared analogously from 1-trifluoroacetyl-5-aminoindoline and the appropriate acid chloride or chloroformate:

N-[4-氯-1-(2，2，2-三氟乙酰基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基N-[4-chloro-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethyl 丁酰胺Butanamide

由1-三氟乙酰基-4-氯-5-氨基二氢吲哚制备。将所述反应混合物蒸发并且无需鉴定用于下一步。Prepared from 1-trifluoroacetyl-4-chloro-5-aminoindoline. The reaction mixture was evaporated and used in the next step without identification.

2，2-二甲基-N-[1-(2，2，2-三氟乙酰基)-2，3-二氢-1H-吲哚-5-基]-丙酰2,2-Dimethyl-N-[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]-propionyl 胺amine

1H NMR(DMSO-d6)：1.22(s，9H)，3.23(t，2H)，4.28(t，2H)，7.47(dd，1H)，7.71(s，1H)，7.96(d，1H)，9.26(s，1H，NHCO). 1 H NMR (DMSO-d 6 ): 1.22(s, 9H), 3.23(t, 2H), 4.28(t, 2H), 7.47(dd, 1H), 7.71(s, 1H), 7.96(d, 1H ), 9.26(s, 1H, NHCO).

2-(4-氟苯基)-N-[1-(2，2，2-三氟乙酰基)-2，3-二氢-1H-吲哚-5-基]-乙2-(4-fluorophenyl)-N-[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]-ethyl 酰胺Amide

LC/MS(m/z)367.0([M+1]+)；RT＝3.00，UV，ELSD)92％，99％.1H NMR(DMSO-d6)：3.22(t，2H)，3.63(s，2H)，4.27(t，2H)，7.15(t，2H)，7.36(dd，2H)，7.39(dd，1H)，7.69(s，1H)，7.97(d，1H)，10.24(s，1H，NHCO).LC/MS (m/z) 367.0 ([M+1] + ); RT=3.00, UV, ELSD) 92%, 99%. 1 H NMR (DMSO-d 6 ): 3.22 (t, 2H), 3.63 (s, 2H), 4.27(t, 2H), 7.15(t, 2H), 7.36(dd, 2H), 7.39(dd, 1H), 7.69(s, 1H), 7.97(d, 1H), 10.24( s, 1H, NHCO).

[1-(2，2，2-三氟乙酰基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸乙酯[1-(2,2,2-Trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]-urethane

使用1，2-二氯乙烷作为溶剂和吡啶作为碱制备标题化合物。The title compound was prepared using 1,2-dichloroethane as solvent and pyridine as base.

LC/MS(m/z)302.1([M]+)；RT＝2.85(UV，ELSD)79％，100％.1H NMR(DMSO-d6)：1.24(t，3H)，3.22(t，2H)，4.12(q，2H)，4.26(t，2H)，7.31(br.d(unresolved dd)，1H)，7.49(s，1H)，7.94(d，1H)，9.70(s，1H，NHCO).LC/MS (m/z) 302.1 ([M] + ); RT = 2.85 (UV, ELSD) 79%, 100%. 1 H NMR (DMSO-d 6 ): 1.24 (t, 3H), 3.22 (t , 2H), 4.12(q, 2H), 4.26(t, 2H), 7.31(br.d(unresolved dd), 1H), 7.49(s, 1H), 7.94(d, 1H), 9.70(s, 1H , NHCO).

[1-(2，2，2-三氟乙酰基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸丙酯[1-(2,2,2-Trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]-carbamic acid propyl ester

使用1，2-二氯乙烷作为溶剂和吡啶作为碱制备标题化合物。The title compound was prepared using 1,2-dichloroethane as solvent and pyridine as base.

LC/MS(m/z)315.9([M]+)；RT＝3.11(UV，ELSD)89％，99％.1H NMR(DMSO-d6)：0.93(t，3H)，1.64(m，2H)，3.22(t，2H)，4.03(t，2H)，4.26(t，2H)，7.32(br.d(unresolved dd)，1H)，7.50(s，1H)，7.94(d，1H)，9.71(s，1H，NHCO).LC/MS (m/z) 315.9 ([M] + ); RT = 3.11 (UV, ELSD) 89%, 99%. 1 H NMR (DMSO-d 6 ): 0.93 (t, 3H), 1.64 (m , 2H), 3.22(t, 2H), 4.03(t, 2H), 4.26(t, 2H), 7.32(br.d(unresolved dd), 1H), 7.50(s, 1H), 7.94(d, 1H ), 9.71(s, 1H, NHCO).

                通式XXV和XXVI中间体的制备Preparation of intermediates of general formula XXV and XXVI

3，3-二甲基-N-(6-硝基-2，3-二氢-1H-吲哚-5-基)-丁酰胺3,3-Dimethyl-N-(6-nitro-2,3-dihydro-1H-indol-5-yl)-butanamide

在5分钟内往冷(冰/水浴)的搅拌的3，3-二甲基-N-[1-(2，2，2-三氟乙酰基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺(1.96g，5.98mmol)在乙酸酐(30ml)和乙酸(5ml)中的溶液中滴加发烟HNO3(650mg，10.3mmol)的乙酸(5ml)溶液。5分钟后将该反应混合物倾入冰中并用固体NaHCO3中和(少量分次加入并搅拌直到停止产生气体)。过滤，水洗并真空干燥，得到黄色固体状的3，3-二甲基-N-[6-硝基-1-(2，2，2-三氟乙酰基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺。Add to cold (ice/water bath) stirred 3,3-dimethyl-N-[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indole over 5 minutes To a solution of indol-5-yl]-butanamide (1.96g, 5.98mmol) in acetic anhydride (30ml) and acetic acid (5ml) was added dropwise a solution of fuming HNO3 (650mg, 10.3mmol) in acetic acid (5ml). After 5 min the reaction mixture was poured into ice and neutralized with solid NaHCO3 (added in small portions and stirred until gas evolution ceased). Filtration, washing with water and drying in vacuo afforded 3,3-dimethyl-N-[6-nitro-1-(2,2,2-trifluoroacetyl)-2,3-dihydro- 1H-indol-5-yl]-butanamide.

LC/MS(m/z)374.0([M+1]+)；RT＝3.45(UV，ELSD)94％，99％.1H NMR(DMSO-d6)：1.03(s，9H)，2.23(s，2H)，3.35(t，2H)，4.36(t，2H)，7.66(s，1H)，7.51(s，1H)，10.17(s，1H，NHCO).LC/MS (m/z) 374.0 ([M+1] + ); RT=3.45 (UV, ELSD) 94%, 99%. 1 H NMR (DMSO-d 6 ): 1.03 (s, 9H), 2.23 (s, 2H), 3.35(t, 2H), 4.36(t, 2H), 7.66(s, 1H), 7.51(s, 1H), 10.17(s, 1H, NHCO).

将该固体重新溶解在甲醇(30ml)中，随后加入K2CO3(2.0g)的水(7ml)溶液。颜色立即由黄色变为深红色。搅拌15分钟后，将该反应混合物倾入冰/水中，过滤分离，得到紫色固体状的标题化合物1.52g，收率为91.8％。The solid was redissolved in methanol (30ml) followed by the addition of K2CO3 ( 2.0g ) in water (7ml). The color changed from yellow to deep red immediately. After stirring for 15 minutes, the reaction mixture was poured into ice/water and separated by filtration to obtain 1.52 g of the title compound as a purple solid with a yield of 91.8%.

LC/MS(m/z)277.0([M]+)；RT＝2.30(UV，ELSD)91％，99％.1H NMR(CDCl3)：1.10(s，9H)，2.29(s，2H)，3.10(t，2H)，3.63(t，2H)，4.80(very br.s，NH)，7.30(s，1H)，8.46(s，1H)，10.14(s，1H，NHCO).LC/MS (m/z) 277.0 ([M] + ); RT = 2.30 (UV, ELSD) 91%, 99%. 1 H NMR (CDCl 3 ): 1.10 (s, 9H), 2.29 (s, 2H ), 3.10(t, 2H), 3.63(t, 2H), 4.80(very br.s, NH), 7.30(s, 1H), 8.46(s, 1H), 10.14(s, 1H, NHCO).

类似地制备如下化合物：The following compounds were prepared analogously:

2，2-二甲基-N-(6-硝基-2，3-二氢-1H-吲哚-5-基)-丙酰胺2,2-Dimethyl-N-(6-nitro-2,3-dihydro-1H-indol-5-yl)-propionamide

LC/MS(m/z)264.1([M+1]+)；RT＝2.19(UV，ELSD)96％，95％.1H NMR(DMSO-d6)：1.19(s，9H)，3.00(t，2H)，3.51(dt，2H)，5.98(br.s，NH)，6.97(s，1H)，7.44(s，1H)，9.57(s，1H，NHCO).LC/MS (m/z) 264.1 ([M+1] + ); RT = 2.19 (UV, ELSD) 96%, 95%. 1 H NMR (DMSO-d 6 ): 1.19 (s, 9H), 3.00 (t, 2H), 3.51(dt, 2H), 5.98(br.s, NH), 6.97(s, 1H), 7.44(s, 1H), 9.57(s, 1H, NHCO).

2-(4-氟苯基)-N-(6-硝基-2，3-二氢-1H-吲哚-5-基)-乙酰胺2-(4-fluorophenyl)-N-(6-nitro-2,3-dihydro-1H-indol-5-yl)-acetamide

LC/MS(m/z)315.0([M]+)；RT＝2.33(UV，ELSD)87％，99％.1H NMR(DMSO-d6)：2.99(t，2H)，3.49(dt，2H)，3.62(s，2H)，6.00(br.s，NH)，6.91(s，1H)，7.15(t，2H)，7.28(s，1H)，7.33(dd，2H)，9.95(s，1H，NHCO).LC/MS (m/z) 315.0 ([M] + ); RT = 2.33 (UV, ELSD) 87%, 99%. 1 H NMR (DMSO-d 6 ): 2.99 (t, 2H), 3.49 (dt , 2H), 3.62(s, 2H), 6.00(br.s, NH), 6.91(s, 1H), 7.15(t, 2H), 7.28(s, 1H), 7.33(dd, 2H), 9.95( s, 1H, NHCO).

[6-硝基-2，3-二氢-1H-吲哚-5-基]-氨基甲酸乙酯[6-Nitro-2,3-dihydro-1H-indol-5-yl]-urethane

LC/MS(m/z)250.9([M]+)；RT＝1.92(UV，ELSD)93％，98％.1H NMR(DMSO-d6)：1.19(t，3H)，2.99(t，2H)，3.50(dt，2H)，4.06(q，2H)，5.96(br.s，NH)，6.92(s，1H)，7.24(s，1H)，9.22(s，1H，NHCO).LC/MS (m/z) 250.9 ([M] + ); RT = 1.92 (UV, ELSD) 93%, 98%. 1 H NMR (DMSO-d 6 ): 1.19 (t, 3H), 2.99 (t , 2H), 3.50(dt, 2H), 4.06(q, 2H), 5.96(br.s, NH), 6.92(s, 1H), 7.24(s, 1H), 9.22(s, 1H, NHCO).

[6-硝基-2，3-二氢-1H-吲哚-5-基]-氨基甲酸丙酯[6-Nitro-2,3-dihydro-1H-indol-5-yl]-carbamate propyl ester

LC/MS(m/z)264.9([M]+)；RT＝2.36(UV，ELSD)93％，99％.1H NMR(DMSO-d6)：0.89(t，3H)，1.59(m，2H)，2.99(t，2H)，3.50(t，2H)，3.97(t，2H)，5.96(br.s，NH)，6.92(s，1H)，7.24(s，1H)，9.22(s，1H，NHCO).LC/MS (m/z) 264.9 ([M] + ); RT = 2.36 (UV, ELSD) 93%, 99%. 1 H NMR (DMSO-d 6 ): 0.89 (t, 3H), 1.59 (m , 2H), 2.99(t, 2H), 3.50(t, 2H), 3.97(t, 2H), 5.96(br.s, NH), 6.92(s, 1H), 7.24(s, 1H), 9.22( s, 1H, NHCO).

3，3-二甲基-N-(6-溴-2，3-二氢-1H-吲哚-5-基)-丁酰胺3,3-Dimethyl-N-(6-bromo-2,3-dihydro-1H-indol-5-yl)-butanamide

往搅拌的3，3-二甲基-N-[1-(2，2，2-三氟乙酰基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺(0.624g，1.90mmol)的乙酸(20ml)溶液中加入溴(0.195ml，1当量)。45分钟后加入更多溴(0.195ml)。将该反应混合物倾入Na2SO3(5g)的水(100ml)溶液中。经过滤、用饱和NaHCO3水溶液和水洗涤分离产物，最终得到无色固体状的N-[6-溴-1-(2，2，2-三氟乙酰基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺0.555g，收率为71％。To stirred 3,3-dimethyl-N-[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]-butanamide (0.624 g, 1.90 mmol) in acetic acid (20 ml) was added bromine (0.195 ml, 1 equiv). After 45 minutes more bromine (0.195ml) was added. The reaction mixture was poured into a solution of Na2SO3 (5g) in water (100ml). After filtration, washing with saturated NaHCO 3 aqueous solution and water to isolate the product, N-[6-bromo-1-(2,2,2-trifluoroacetyl)-2,3-dihydro- 0.555 g of 1H-indol-5-yl]-3,3-dimethylbutyramide, the yield was 71%.

LC/MS(m/z)409.0([M+1]+)；RT＝3.38(UV，ELSD)97.5％，85.5％.1H NMR(DMSO-d6)：1.05(s，9H)，2.25(s，2H)，3.22(t，2H)，4.30(t，2H)，7.55(s，1H)，8.25(s，1H)，9.37(s，1H，NHCO).LC/MS (m/z) 409.0 ([M+1] + ); RT=3.38 (UV, ELSD) 97.5%, 85.5%. 1 H NMR (DMSO-d 6 ): 1.05 (s, 9H), 2.25 (s, 2H), 3.22(t, 2H), 4.30(t, 2H), 7.55(s, 1H), 8.25(s, 1H), 9.37(s, 1H, NHCO).

将该固体(100mg)重新溶解在甲醇(10ml)中，随后加入K2CO3(0.52g)的水(5ml)溶液。在50℃下搅拌5分钟后，将该反应混合物倾入冰/水混合物中，通过过滤分离得到无色固体状标题化合物0.057g，收率为75％。The solid (100mg) was redissolved in methanol (10ml) followed by the addition of K2CO3 ( 0.52g ) in water (5ml). After stirring at 50°C for 5 minutes, the reaction mixture was poured into an ice/water mixture and the title compound was isolated by filtration to give 0.057 g of the title compound as a colorless solid, yield 75%.

LC/MS(m/z)313.0([M+1]+)；RT＝1.71，(UV，ELSD)97.5％，98.9％.LC/MS (m/z) 313.0 ([M+1] + ); RT=1.71, (UV, ELSD) 97.5%, 98.9%.

                  通式XVIII中间体的制备Preparation of intermediate of general formula XVIII

N-(4-氯-2，3-二氢-1H-吲哚-5-基)-3，3-二甲基丁酰胺N-(4-chloro-2,3-dihydro-1H-indol-5-yl)-3,3-dimethylbutanamide

往粗制的N-[4-氯-1-(2，2，2-三氟乙酰基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺(约100mg)的MeOH(10ml)溶液中加入K2CO3(0.5g)的水(2ml)溶液。在50℃将得到的混合物加热5分钟，随后用乙酸乙酯和水猝灭。该有机溶液经SiO2(5g)过滤并真空蒸发，得到标题化合物20mg。该粗产品不需纯化用于下一步。To crude N-[4-chloro-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethyl To a solution of butanamide (about 100 mg) in MeOH (10 ml) was added a solution of K2CO3 (0.5 g) in water (2 ml). The resulting mixture was heated at 50°C for 5 minutes, then quenched with ethyl acetate and water. The organic solution was filtered through SiO2 (5g) and evaporated in vacuo to give the title compound 20mg. The crude product was used in the next step without purification.

LC/MS(m/z)267.1([M+1]+)；RT＝1.61(UV，ELSD)45％，78％.LC/MS (m/z) 267.1 ([M+1] + ); RT=1.61 (UV, ELSD) 45%, 78%.

N-(2，3-二氢-1H-吲哚-5-基)-2-(4-氟苯基)-乙酰胺N-(2,3-Dihydro-1H-indol-5-yl)-2-(4-fluorophenyl)-acetamide

往2-(4-氟苯基)-N-[1-(2，2，2-三氟乙酰基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺(1.3g，3.55mmol)的甲醇(50ml)溶液中加入K2CO3(7.6g)的水(20ml)溶液。该反应混合物在50℃保温5分钟，随后倾入水中，经过滤分离得到标题化合物0.742g，收率为77.4％。To 2-(4-fluorophenyl)-N-[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]-acetamide (1.3 g, 3.55mmol) in methanol (50ml) was added K 2 CO 3 (7.6g) in water (20ml). The reaction mixture was kept at 50°C for 5 minutes, then poured into water, and separated by filtration to obtain 0.742 g of the title compound with a yield of 77.4%.

LC/MS(m/z)271.0([M+1]+)；RT＝1.42，(UV，ELSD)94.5％，98.7％.1H NMR(DMSO-d6)：2.85(t，2H)，3.36(t，2H)，3.55(s，2H)；5.28(br，1H，NH)；6.41(d，1H)；7.06(dd，1H)；7.12(t，2H)；7.28(d，1H)；7.35(dd，2H)；9.75(s，1H，NHCO).LC/MS (m/z) 271.0 ([M+1] + ); RT=1.42, (UV, ELSD) 94.5%, 98.7%. 1 H NMR (DMSO-d 6 ): 2.85 (t, 2H), 3.36(t, 2H), 3.55(s, 2H); 5.28(br, 1H, NH); 6.41(d, 1H); 7.06(dd, 1H); 7.12(t, 2H); 7.28(d, 1H) ; 7.35 (dd, 2H); 9.75 (s, 1H, NHCO).

类似地由3，3-二甲基-N-[1-(2，2，2-三氟乙酰基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺制备如下化合物：Prepared analogously from 3,3-dimethyl-N-[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]-butanamide as follows Compound:

N-(2，3-二氢-1H-吲哚-5-基)-3，3-二甲基-丁酰胺N-(2,3-Dihydro-1H-indol-5-yl)-3,3-dimethyl-butanamide

LC/MS(m/z)232.9([M+1]+)；RT＝1.43，(UV，ELSD)94.4％，88.1％.1H NMR(DMSO-d6)：1.00(s，9H)；2.09(s，2H)；2.84(t，2H)；3.37(t，2H)；5.25(br，1H，NH)；6.41(d，1H)；7.02(dd，1H)；7.29(d，1H)；9.34(s，1H，NHCO).LC/MS (m/z) 232.9 ([M+1] + ); RT=1.43, (UV, ELSD) 94.4%, 88.1%. 1 H NMR (DMSO-d 6 ): 1.00 (s, 9H); 2.09(s, 2H); 2.84(t, 2H); 3.37(t, 2H); 5.25(br, 1H, NH); 6.41(d, 1H); 7.02(dd, 1H); 7.29(d, 1H) ; 9.34 (s, 1H, NHCO).

                   本发明的化合物Compounds of the present invention

                      实施例1Example 1

1a N-[4-氯-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲1a N-[4-chloro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethyl 基丁酰胺butyramide

往N-(4-氯-2，3-二氢-1H-吲哚-5-基)-3，3-二甲基丁酰胺(10mg)、4-三氟甲基苯甲醛(0.06ml)和乙酸(0.03ml)的甲醇(0.3ml)溶液中加入NaBH3CN(100mg)。60分钟后，将反应混合物在乙酸乙酯和饱和NaHCO3水溶液之间分配。该有机层经SiO2(2g)柱塞过滤，蒸发，并通过制备型LC/MS纯化，得到无色固体状的标题化合物11mg。To N-(4-chloro-2,3-dihydro-1H-indol-5-yl)-3,3-dimethylbutanamide (10mg), 4-trifluoromethylbenzaldehyde (0.06ml) To a solution of acetic acid (0.03ml) in methanol (0.3ml) was added NaBH3CN (100mg). After 60 minutes, the reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO 3 . The organic layer was filtered through a plug of SiO2 (2g), evaporated and purified by preparative LC/MS to afford the title compound as a colorless solid, 11 mg.

LC/MS(m/z)425.2([M+1]+)；RT＝4.01，(UV，ELSD)95％，99％.1H NMR(DMSO-d6)：1.03(s，9H)，2.16(s，2H)，2.97(t，2H)，3.40(t，2H)，4.41(s，2H)，6.48(d，1H)，7.03(d，1H)，7.56(d，2H)，7.72(d，2H)，9.12(s，1H，NHCO).LC/MS (m/z) 425.2 ([M+1] + ); RT=4.01, (UV, ELSD) 95%, 99%. 1 H NMR (DMSO-d 6 ): 1.03 (s, 9H), 2.16(s, 2H), 2.97(t, 2H), 3.40(t, 2H), 4.41(s, 2H), 6.48(d, 1H), 7.03(d, 1H), 7.56(d, 2H), 7.72 (d, 2H), 9.12 (s, 1H, NHCO).

类似地使用5-氯-2-噻吩甲醛制备如下化合物：The following compounds were prepared similarly using 5-chloro-2-thiophenecarbaldehyde:

1b N-[4-氯-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二1b N-[4-chloro-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-di 甲基丁酰胺Methylbutanamide

LC/MS(m/z)397.0(M+1]+)；RT＝3.91，(UV，ELSD)97％，99％.1H NMR(DMSO-d6)：1.03(s，9H)，2.17(s，2H)，2.92(t，2H)，3.37(t，2H)，4.46(s，2H)，6.60(d，1H)，6.95(d，1H)，6.99(d，1H)，7.07(d，1H)，9.12(s，1H，NHCO).LC/MS (m/z) 397.0 (M+1] + ); RT = 3.91, (UV, ELSD) 97%, 99%. 1 H NMR (DMSO-d 6 ): 1.03 (s, 9H), 2.17 (s, 2H), 2.92(t, 2H), 3.37(t, 2H), 4.46(s, 2H), 6.60(d, 1H), 6.95(d, 1H), 6.99(d, 1H), 7.07( d, 1H), 9.12 (s, 1H, NHCO).

                       实施例2Example 2

2a[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸丙酯往冷(冰/水浴)的1-(4-氟苄基)-5-氨基二氢吲哚的乙腈溶液(0.2M，0.15ml)中加入氯甲酸丙酯(0.02ml或约20mg)，随后加入吡啶(0.03ml)。在室温下将该反应混合物放置60分钟，随后真空蒸发。通过制备型LC/MS分离，得到标题化合物5.8mg，收率为59％。LC/MS(m/z)329.1([M+1]+)；RT＝2.68，(UV，ELSD)94％，99％。 2a[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-carbamate propyl ester to cold (ice/water bath) 1-(4-fluorobenzyl) - To a solution of 5-aminoindoline in acetonitrile (0.2M, 0.15ml) was added propyl chloroformate (0.02ml or about 20mg) followed by pyridine (0.03ml). The reaction mixture was left at room temperature for 60 minutes, then evaporated in vacuo. Separation by preparative LC/MS afforded 5.8 mg of the title compound in a yield of 59%. LC/MS (m/z) 329.1 ([M+1] + ); RT = 2.68, (UV, ELSD) 94%, 99%.

类似地由相应的5-氨基二氢吲哚和市售的合适的氯甲酸酯、氨基甲酰氯、磺酰氯、酰氯、二碳酸二叔丁酯(Boc2O)或异氰酸酯得到以下化合物，这些化合物列在下表1中。在使用氯甲酸酯、氨基甲酰氯和磺酰氯的情况下，使用吡啶作为碱。在使用酰氯的情况下，使用三乙胺作为碱。在使用异氰酸酯和Boc2O的情况下，不使用碱。The following compounds are obtained analogously from the corresponding 5-aminoindoline and the commercially available appropriate chloroformate, carbamoyl chloride, sulfonyl chloride, acid chloride, di-tert-butyl dicarbonate ( Boc2O ) or isocyanate, which The compounds are listed in Table 1 below. In the case of chloroformates, carbamoyl chlorides and sulfonyl chlorides, pyridine is used as base. In the case of using acid chlorides, triethylamine is used as base. In the case of isocyanate and Boc 2 O, no base is used.

2b N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-C-苯基-甲磺酰胺2b N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-C-phenyl-methanesulfonamide

LC/MS(m/z)395.3([M-1]+)；RT＝3.17，(UV，ELSD)80％，100％。LC/MS (m/z) 395.3 ([M-1] + ); RT = 3.17, (UV, ELSD) 80%, 100%.

2c 4-氟-N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-苯甲酰胺2c 4-fluoro-N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-benzamide

LC/MS(m/z)365.4([M+1]+)；RT＝2.90，(UV，ELSD)96％，100％。LC/MS (m/z) 365.4 ([M+1] + ); RT = 2.90, (UV, ELSD) 96%, 100%.

2d N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺2d N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide

LC/MS(m/z)341.1([M+1]+)；RT＝2.79，(UV，ELSD)94％，100％。LC/MS (m/z) 341.1 ([M+1] + ); RT = 2.79, (UV, ELSD) 94%, 100%.

2e N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-2-噻吩-2-基乙酰胺2e N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-2-thiophen-2-ylacetamide

LC/MS(m/z)367.1([M+1]+)；RT＝2.72，(UV，ELSD)93％，100％。LC/MS (m/z) 367.1 ([M+1] + ); RT = 2.72, (UV, ELSD) 93%, 100%.

2f N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺2f N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide

LC/MS(m/z)379.3([M+1]+)；RT＝2.82，(UV，ELSD)95％，100％。LC/MS (m/z) 379.3 ([M+1] + ); RT = 2.82, (UV, ELSD) 95%, 100%.

2g 3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-1，1-二异丙2g 3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-1,1-diisopropyl 基脲Urea

LC/MS(m/z)392.3([M+1]+)；RT＝3.14，(UV，ELSD)75％，89％。LC/MS (m/z) 392.3 ([M+1] + ); RT = 3.14, (UV, ELSD) 75%, 89%.

2h N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-吗啉-4-甲2h N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-morpholine-4-methanol 酰胺Amide

LC/MS(m/z)378.2([M+1]+)；RT＝2.33，(UV，ELSD)97％，100％。LC/MS (m/z) 378.2 ([M+1] + ); RT = 2.33, (UV, ELSD) 97%, 100%.

2i N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-吡咯烷-1-甲2i N-[1-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-pyrrolidin-1-methyl 酰胺Amide

LC/MS(m/z)362.0([M+1]+)；RT＝2.48，(UV，ELSD)83％，99％。LC/MS (m/z) 362.0 ([M+1] + ); RT = 2.48, (UV, ELSD) 83%, 99%.

2j [1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸2-苄2j [1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-carbamic acid 2-benzyl 氧基乙酯Oxyethyl ester

LC/MS(m/z)442.1([M]+)；RT＝3.52，(UV，ELSD)62％，86％。LC/MS (m/z) 442.1 ([M] + ); RT = 3.52, (UV, ELSD) 62%, 86%.

2k 3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-1-甲基-1-丙2k 3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1-propane 基脲Urea

LC/MS(m/z)364.3([M+1]+)；RT＝2.73，(UV，ELSD)94％，100％。LC/MS (m/z) 364.3 ([M+1] + ); RT = 2.73, (UV, ELSD) 94%, 100%.

2l [1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸叔丁2l [1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-tert-butyl carbamate 酯ester

LC/MS(m/z)364.3([M]+)；RT＝3.50，(UV，ELSD)97％，100％。LC/MS (m/z) 364.3 ([M] + ); RT = 3.50, (UV, ELSD) 97%, 100%.

2m N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-C-苯基-甲2m N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-C-phenyl-methyl 磺酰胺Sulfonamide

LC/MS(m/z)418.2([M]+)；RT＝3.44，(UV，ELSD)98％，100％。LC/MS (m/z) 418.2 ([M] + ); RT = 3.44, (UV, ELSD) 98%, 100%.

2n N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁烷-1-磺2n N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butane-1-sulfonate 酰胺Amide

LC/MS(m/z)384.1([M]+)；RT＝3.43，(UV，ELSD)98％，100％。LC/MS (m/z) 384.1 ([M] + ); RT = 3.43, (UV, ELSD) 98%, 100%.

2o N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-4-氟苯甲酰2o N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-4-fluorobenzoyl 胺amine

LC/MS(m/z)386.0([M]+)；RT＝3.35，(UV，ELSD)91％，100％。LC/MS (m/z) 386.0 ([M] + ); RT = 3.35, (UV, ELSD) 91%, 100%.

2p N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2，2-二甲基2p N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2,2-dimethyl 丙酰胺Propionamide

LC/MS(m/z)349.0([M+1]+)；RT＝3.21，(UV，ELSD)94％，100％。LC/MS (m/z) 349.0 ([M+1] + ); RT = 3.21, (UV, ELSD) 94%, 100%.

2q N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-苯氧基乙2q N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2-phenoxyethyl 酰胺Amide

LC/MS(m/z)398.0([M]+)；RT＝3.46，(UV，ELSD)80％，100％。LC/MS (m/z) 398.0 ([M] + ); RT = 3.46, (UV, ELSD) 80%, 100%.

2r N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基2r N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethyl 丁酰胺Butanamide

LC/MS(m/z)362.1([M]+)；RT＝3.34，(UV，ELSD)84％，99％。LC/MS (m/z) 362.1 ([M] + ); RT = 3.34, (UV, ELSD) 84%, 99%.

2s N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺2s N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butanamide

LC/MS(m/z)335.0([M+1]+)；RT＝2.95，(UV，ELSD)78％，99％。LC/MS (m/z) 335.0 ([M+1] + ); RT = 2.95, (UV, ELSD) 78%, 99%.

2t N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-环戊烷甲酰2t N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-cyclopentanecarbonyl 胺amine

LC/MS(m/z)361.1([M+1]+)；RT＝3.22，(UV，ELSD)84％，99％。LC/MS (m/z) 361.1 ([M+1] + ); RT = 3.22, (UV, ELSD) 84%, 99%.

2u N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-噻吩-2-基2u N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2-thiophen-2-yl 乙酰胺Acetamide

LC/MS(m/z)388.1([M]+)；RT＝3.22，(UV，ELSD)76％，98％。LC/MS (m/z) 388.1 ([M] + ); RT = 3.22, (UV, ELSD) 76%, 98%.

2v N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-异烟酰胺2v N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-isonicotinamide

LC/MS(m/z)370.0([M+1]+)；RT＝2.22，(UV，ELSD)96％，100％。LC/MS (m/z) 370.0 ([M+1] + ); RT = 2.22, (UV, ELSD) 96%, 100%.

2w N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-4-二甲基2w N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-4-dimethyl 氨基苯甲酰胺Aminobenzamide

LC/MS(m/z)412.0([M+1]+)；RT＝3.09，(UV，ELSD)87％，100％。LC/MS (m/z) 412.0 ([M+1] + ); RT = 3.09, (UV, ELSD) 87%, 100%.

2x N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯2x N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorobenzene 基)-乙酰胺base)-acetamide

LC/MS(m/z)401.0([M+1]+)；RT＝3.31，(UV，ELSD)84％，100％。LC/MS (m/z) 401.0 ([M+1] + ); RT = 3.31, (UV, ELSD) 84%, 100%.

2y N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-6-三氟甲基2y N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-6-trifluoromethyl 烟酰胺Nicotinamide

LC/MS(m/z)437.1([M]+)；RT＝3.46，(UV，ELSD)90％，99％。LC/MS (m/z) 437.1 ([M] + ); RT = 3.46, (UV, ELSD) 90%, 99%.

2z 1-叔丁基-3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-脲2z 1-tert-butyl-3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-urea

LC/MS(m/z)364.3([M+1]+)；RT＝2.80，(UV，ELSD)97％，100％。LC/MS (m/z) 364.3 ([M+1] + ); RT = 2.80, (UV, ELSD) 97%, 100%.

2aa 1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-乙基脲2aa 1-[1-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-ethylurea

LC/MS(m/z)335.1([M]+)；RT＝2.34，(UV，ELSD)96％，100％。LC/MS (m/z) 335.1 ([M] + ); RT = 2.34, (UV, ELSD) 96%, 100%.

2ab 1-苄基-3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-脲2ab 1-Benzyl-3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-urea

LC/MS(m/z)398.2([M+1]+)；RT＝2.85，(UV，ELSD)84％，100％。LC/MS (m/z) 398.2 ([M+1] + ); RT = 2.85, (UV, ELSD) 84%, 100%.

2ac 1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-苯乙基脲2ac 1-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-phenylethylurea

LC/MS(m/z)411.9([M+1]+)；RT＝3.00，(UV，ELSD)87％，97％。LC/MS (m/z) 411.9 ([M+1] + ); RT = 3.00, (UV, ELSD) 87%, 97%.

2ad 1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-噻吩-2-2ad 1-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-thiophene-2- 基脲Urea

LC/MS(m/z)390.0([M+1]+)；RT＝3.01，(UV，ELSD)94％，92％。LC/MS (m/z) 390.0 ([M+1] + ); RT = 3.01, (UV, ELSD) 94%, 92%.

2ae 1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-噻吩-3-2ae 1-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-thiophene-3- 基脲Urea

LC/MS(m/z)390.2([M+1]+)；RT＝2.98，(UV，ELSD)96％，100％。LC/MS (m/z) 390.2 ([M+1] + ); RT = 2.98, (UV, ELSD) 96%, 100%.

2af [1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸丙2af [1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-carbamate propane 酯ester

LC/MS(m/z)351.2([M]+)；RT＝3.48，(UV，ELSD)94.0％，98.0％.1H NMR(DMSO-d6)：0.92(t，3H)；1.62(sextet，2H)；2.84(t，2H)；3.22(t，2H)，3.89(t，2H)，4.38(s，2H)，6.59(d，1H)；6.92(d，1H)；6.98(d，1H)；7.07(br.d(dd)，1H)；7.18(br.s，1H)；9.20(brs，1H，NH).LC/MS (m/z) 351.2 ([M] + ); RT = 3.48, (UV, ELSD) 94.0%, 98.0%. 1 H NMR (DMSO-d 6 ): 0.92 (t, 3H); 1.62 ( sextet, 2H); 2.84(t, 2H); 3.22(t, 2H), 3.89(t, 2H), 4.38(s, 2H), 6.59(d, 1H); 6.92(d, 1H); 6.98(d , 1H); 7.07 (br.d(dd), 1H); 7.18 (br.s, 1H); 9.20 (brs, 1H, NH).

表1.在本发明2a-2af化合物的制备中使用的氯甲酸酯、磺酰氯、氨基甲酰氯、酰氯和异氰酸酯   本发明的化合物   试剂   分子量   厂商   目录号   2a   氯甲酸正丙酯   122.55   Aldrich   24，946-7   2b   α-甲苯磺酰氯   190.649   Aldrich   15，971-9   2c   4-氟苯甲酰氯   158.559   Aldrich   11，994-6   2d   叔丁基乙酰氯   134.605   Aldrich   B8，880-2   2e   噻吩-2-乙酰氯   160.624   Aldrich   19，599-5   2f   4-氟苯基乙酰氯   172.585   Aldrich   46，695-6   2g   二异丙基氨基甲酰氯   163.647   Aldrich   S31，027-1   2h   吗啉-4-甲酰氯   149.576   Aldrich   34，829-5   2i   1-吡咯烷甲酰氯   133.577   Aldrich   20，635-0   2j   氯甲酸2-苄氧基乙酯   214.647   Aldrich   52，514-6   2k   N-异丙基-N-甲基-氨基甲酰氯   135.59   Lundbeck   C0005221   2l   二碳酸二叔丁酯   218.247   Fluka   34660   2m   α-甲苯磺酰氯   190.649   Aldrich   15，971-9   2n   丁磺酰氯   156.632   Aldrich   26，360-5   2o   4-氟苯甲酰氯   158.559   Aldrich   11，994-6   2p   三甲基乙酰氯   120.578   Aldrich   T7，260-5   2q   苯氧基乙酰氯   170.594   Aldrich   15，862-3   2r   叔丁基乙酰氯   134.605   Aldrich   B8，880-2   2s   丁酰氯   106.551   Aldrich   10，961-4   2t   环戊烷甲酰氯   132.589   Aldrich   32，831-6   2u   噻吩-2-乙酰氯   160.624   Aldrich   19，599-5   2v   异烟酰氯盐酸盐   178.018   Aldrich   22，875-3   2w   4-二甲基氨基苯甲酰氯   183.637   Aldrich   52，611-8   2x   4-氟苯基乙酰氯   172.585   Aldrich   46，695-6   2y   6-(三氟甲基)烟酰氯   209.554   Fluorochem   9368   2z   异氰酸叔丁酯   99.132   Aldrich   14，445-2   2aa   异氰酸乙酯   71.08   Aldrich   E3，330-0   2ab   异氰酸苄酯   133.149   Aldrich   22，726-9   2ac   异氰酸苯乙酯   147.176   Aldrich   45，617-9   2ad   异氰酸2-噻吩酯   125.151   Maybridge   CC13006   2ae   异氰酸3-噻吩酯   125.151   Maybridge   CC13106   2af   氯甲酸正丙酯   122.55   Aldrich   24，946-7 Table 1. Chloroformates, Sulfonyl Chlorides, Carbamoyl Chlorides, Acid Chlorides and Isocyanates Used in the Preparation of Compounds 2a-2af of the Invention Compounds of the invention Reagent molecular weight manufacturers catalog number 2a n-Propyl Chloroformate 122.55 Aldrich 24,946-7 2b α-Toluenesulfonyl chloride 190.649 Aldrich 15,971-9 2c 4-fluorobenzoyl chloride 158.559 Aldrich 11,994-6 2d tert-Butylacetyl chloride 134.605 Aldrich B8,880-2 2e Thiophene-2-acetyl chloride 160.624 Aldrich 19,599-5 2f 4-Fluorophenylacetyl chloride 172.585 Aldrich 46,695-6 2g Diisopropylcarbamoyl chloride 163.647 Aldrich S31,027-1 2 hours Morpholine-4-carbonyl chloride 149.576 Aldrich 34,829-5 2i 1-Pyrrolidinecarbonyl chloride 133.577 Aldrich 20,635-0 2j 2-Benzyloxyethyl chloroformate 214.647 Aldrich 52,514-6 2k N-Isopropyl-N-methyl-carbamoyl chloride 135.59 Lundbeck C0005221 2l Di-tert-butyl dicarbonate 218.247 Fluka 34660 2m α-Toluenesulfonyl chloride 190.649 Aldrich 15,971-9 2n Butanesulfonyl chloride 156.632 Aldrich 26,360-5 2o 4-fluorobenzoyl chloride 158.559 Aldrich 11,994-6 2p Trimethylacetyl chloride 120.578 Aldrich T7, 260-5 2q Phenoxyacetyl chloride 170.594 Aldrich 15,862-3 2r tert-Butylacetyl chloride 134.605 Aldrich B8,880-2 2s Butyryl chloride 106.551 Aldrich 10,961-4 2t Cyclopentanecarbonyl chloride 132.589 Aldrich 32,831-6 2u Thiophene-2-acetyl chloride 160.624 Aldrich 19,599-5 2v Isonicotinoyl Chloride Hydrochloride 178.018 Aldrich 22,875-3 2w 4-Dimethylaminobenzoyl chloride 183.637 Aldrich 52,611-8 2x 4-Fluorophenylacetyl chloride 172.585 Aldrich 46,695-6 2 years 6-(Trifluoromethyl)nicotinoyl chloride 209.554 Fluorochem 9368 2z tert-butyl isocyanate 99.132 Aldrich 14,445-2 2aa Ethyl isocyanate 71.08 Aldrich E3, 330-0 2ab Benzyl isocyanate 133.149 Aldrich 22,726-9 2ac Phenylethyl isocyanate 147.176 Aldrich 45,617-9 2ad 2-thiophene isocyanate 125.151 Maybridge CC13006 2ae 3-thiophene isocyanate 125.151 Maybridge CC13106 2af n-Propyl Chloroformate 122.55 Aldrich 24,946-7

                         实施例3Example 3

3a 2，2-二甲基-N-[6-硝基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-3a 2,2-Dimethyl-N-[6-nitro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indole- 5-基]-丙酰胺5-yl]-propionamide

在3小时内分成4部分往搅拌的2，2-二甲基-N-(6-硝基-2，3-二氢-1H-吲哚-5-基)-丙酰胺(0.379g，1.44mmol)的甲醇(25ml)溶液中加入4-三氟甲基苯甲醛(0.8ml)、乙酸(0.8ml)以及NaBH3CN(0.8g)的甲醇(10ml)溶液直到反应完全。将得到的反应混合物真空浓缩至小体积，用饱和NaHCO3水溶液急冷并超声处理几分钟。经过滤分离，得到红色固体状的标题化合物0.574g，收率为95％。2,2-Dimethyl-N-(6-nitro-2,3-dihydro-1H-indol-5-yl)-propionamide (0.379g, 1.44 mmol) in methanol (25ml) were added 4-trifluoromethylbenzaldehyde (0.8ml), acetic acid (0.8ml) and NaBH 3 CN (0.8g) in methanol (10ml) until the reaction was complete. The resulting reaction mixture was concentrated in vacuo to a small volume, quenched with saturated aqueous NaHCO 3 and sonicated for several minutes. After separation by filtration, 0.574 g of the title compound was obtained as a red solid, with a yield of 95%.

LC/MS(m/z)422.1([M+1]+)；RT＝4.11，(UV，ELSD)96％，99％.1H NMR (DMSO-d6)：1.20(s，9H)，3.04(t，2H)，3.42(t，2H)，4.49(s，2H)，7.09(s，1H)，7.48(s，1H)，7.57(d，2H)，7.73(d，2H)，9.62(s，1H，NHCO).LC/MS (m/z) 422.1 ([M+1] + ); RT=4.11, (UV, ELSD) 96%, 99%. 1 H NMR (DMSO-d 6 ): 1.20 (s, 9H), 3.04(t, 2H), 3.42(t, 2H), 4.49(s, 2H), 7.09(s, 1H), 7.48(s, 1H), 7.57(d, 2H), 7.73(d, 2H), 9.62 (s, 1H, NHCO).

类似地制备如下化合物：The following compounds were prepared analogously:

3b N-[1-(5-氯噻吩-2-基甲基)-6-硝基-2，3-二氢-1H-吲哚-5-基]-2，2-3b N-[1-(5-chlorothien-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indol-5-yl]-2,2- 二甲基丙酰胺Dimethylpropionamide

LC/MS(m/z)394.0([M+1]+；RT＝4.07，(UV，ELSD)97％，98％.1H NMR(DMSO-d6)：1.20(s，9H)，3.00(t，2H)，3.41(t，2H)，4.55(s，2H)，6.97(d，1H)，7.01(d，1H)，7.22(s，1H)，7.47(s，1H)，9.62(s，1H，NHCO).LC/MS (m/z) 394.0 ([M+1] + ; RT=4.07, (UV, ELSD) 97%, 98%. 1 H NMR (DMSO-d 6 ): 1.20 (s, 9H), 3.00 (t, 2H), 3.41(t, 2H), 4.55(s, 2H), 6.97(d, 1H), 7.01(d, 1H), 7.22(s, 1H), 7.47(s, 1H), 9.62( s, 1H, NHCO).

3c 2-(4-氟苯基)-N-[6-硝基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚3c 2-(4-fluorophenyl)-N-[6-nitro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indole -5-基]-乙酰胺-5-yl]-acetamide

LC/MS(m/z)474.2([M+1]+)；RT＝3.89，(UV，ELSD)80％，97％.LC/MS (m/z) 474.2 ([M+1] + ); RT=3.89, (UV, ELSD) 80%, 97%.

3d N-[1-(5-氯噻吩-2-基甲基)-6-硝基-2，3-二氢-1H-吲哚-5-基]-2-3d N-[1-(5-chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indol-5-yl]-2- (4-氟苯基)-乙酰胺(4-Fluorophenyl)-acetamide

LC/MS(m/z)445.1([M]+)；RT＝3.88，(UV，ELSD)79.8％，98.9％.1H NMR(DMSO-d6)：2.98(t，2H)；3.41(t，2H)，3.63(s，2H)，4.54(s，2H)，6.96(d，1H)；7.0(d，1H)；7.16(t，2H)；7.17(s，1H)；7.31(s，1H)；7.34(dd，2H)；10.03(s，1H，NH).LC/MS (m/z) 445.1 ([M] + ); RT = 3.88, (UV, ELSD) 79.8%, 98.9%. 1 H NMR (DMSO-d 6 ): 2.98 (t, 2H); 3.41 ( t, 2H), 3.63(s, 2H), 4.54(s, 2H), 6.96(d, 1H); 7.0(d, 1H); 7.16(t, 2H); 7.17(s, 1H); 7.31(s , 1H); 7.34(dd, 2H); 10.03(s, 1H, NH).

3e N-[1-(5-氯噻吩-2-基甲基)-6-硝基-2，3-二氢-1H-吲哚-5-基]-3，3-3e N-[1-(5-chlorothien-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indol-5-yl]-3,3- 二甲基丁酰胺Dimethylbutanamide

LC/MS(m/z)407.1([M]+)；RT＝4.07，(UV，ELSD)72.4％，98.7％.1H NMR(DMSO-d6)：1.01(s，9H)；2.16(s，2H)；2.99(t，2H)；3.41(t，2H)，4.54(s，2H)，6.98(d，1H)；7.01(d，1H)；7.14(s，1H)；7.23(s，1H)；9.76(s，1H，NH).LC/MS (m/z) 407.1 ([M] + ); RT = 4.07, (UV, ELSD) 72.4%, 98.7%. 1 H NMR (DMSO-d 6 ): 1.01 (s, 9H); 2.16 ( s, 2H); 2.99(t, 2H); 3.41(t, 2H), 4.54(s, 2H), 6.98(d, 1H); 7.01(d, 1H); 7.14(s, 1H); 7.23(s , 1H); 9.76(s, 1H, NH).

                         实施例4Example 4

4a N-[6-氨基-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-4a N-[6-amino-1-(5-chlorothien-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3- 二甲基丁酰胺Dimethylbutanamide

往3，3-二甲基-N-(6-硝基-2，3-二氢-1H-吲哚-5-基)-丁酰胺(15mg)、5-氯-2-噻吩甲醛(50mg)和乙酸(0.1ml)的甲醇(5ml)溶液中加入NaBH3CN(200mg)。30分钟后，将该反应混合物在真空中浓缩至小体积，随后在乙酸乙酯和水之间分配。用1M盐酸和饱和NaHCO3水溶液洗涤该有机溶液并在真空中蒸发。To 3,3-dimethyl-N-(6-nitro-2,3-dihydro-1H-indol-5-yl)-butanamide (15mg), 5-chloro-2-thiophenecarbaldehyde (50mg ) and acetic acid (0.1 ml) in methanol (5 ml) was added NaBH 3 CN (200 mg). After 30 minutes, the reaction mixture was concentrated in vacuo to a small volume, then partitioned between ethyl acetate and water. The organic solution was washed with 1M hydrochloric acid and saturated aqueous NaHCO 3 and evaporated in vacuo.

将得到的残余物溶解在四氢呋喃(10ml)和乙酸(2ml)中，随后加入锌粉(1g)。将得到的悬浮液超声处理5分钟，再加入锌粉(0.5g)并继续超声处理2分钟。经SiO2(2g)柱塞过滤所得到的悬浮液，蒸发，通过制备型LC/MS分离，得到无色固体状的标题化合物6.5mg，收率为32％。The obtained residue was dissolved in tetrahydrofuran (10 ml) and acetic acid (2 ml), and then zinc powder (1 g) was added. The resulting suspension was sonicated for 5 minutes, further zinc powder (0.5 g) was added and sonication was continued for 2 minutes. The resulting suspension was filtered through a plug of SiO2 (2g), evaporated and separated by preparative LC/MS to afford the title compound as a colorless solid, 6.5mg, 32% yield.

LC/MS(m/z)378.0([M+1]+)；RT＝2.36，(UV，ELSD)93％，98％.％.1H NMR(DMSO-d6)：1.03(s，9H)，2.17(s，2H)，2.82(t，2H)，3.30(t，2H)，3.55(很宽s，NH2水)，4.38(s，2H)，6.27(s，1H)，6.81(s，1H)，6.93(d，1H)，7.00(d，1H)，9.27(br.s，1H，NHCO).LC/MS (m/z) 378.0 ([M+1] + ); RT=2.36, (UV, ELSD) 93%, 98%.%. 1 H NMR (DMSO-d 6 ): 1.03 (s, 9H ), 2.17(s, 2H), 2.82(t, 2H), 3.30(t, 2H), 3.55(very wide s, NH 2 water), 4.38(s, 2H), 6.27(s, 1H), 6.81( s, 1H), 6.93 (d, 1H), 7.00 (d, 1H), 9.27 (br.s, 1H, NHCO).

4b N-[6-氨基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-2，2-二4b N-[6-amino-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-2,2-di 甲基丙酰胺Methacrylamide

按照上述制备1-(5-氯噻吩-2-基甲基)-5-氨基二氢吲哚(参见通式XXI中间体的制备)的方法，由上述2，2-二甲基-N-[6-硝基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-丙酰胺(参见实施例3)通过锌粉还原反应制备标题化合物。经SiO2过滤后，用乙酸乙酯和庚烷处理粗的固体残余物，并通过过滤分离得到无色固体状标题化合物0.375g，收率为71％。According to the method for the above-mentioned preparation of 1-(5-chlorothiophen-2-ylmethyl)-5-aminoindoline (see the preparation of intermediates of general formula XXI), from the above-mentioned 2,2-dimethyl-N- [6-Nitro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-propionamide (see Example 3) was prepared by reduction of zinc powder title compound. After filtration over SiO2 , the crude solid residue was treated with ethyl acetate and heptane and isolated by filtration to afford the title compound as a colorless solid, 0.375 g, 71% yield.

LC/MS(m/z)392.3([M+1]+)；RT＝2.38，(UV，ELSD)97％，99％.1H NMR(DMSO-d6)：1.20(s，9H)，2.77(t，2H)，3.25(t，2H)，4.28(s，2H)，4.34(s，2H，NH2)，5.96(s，1H)，6.64(s，1H)，7.56(d，2H)，7.71(d，2H)，8.47(s，1H，NHCO).LC/MS (m/z) 392.3 ([M+1] + ); RT=2.38, (UV, ELSD) 97%, 99%. 1 H NMR (DMSO-d 6 ): 1.20 (s, 9H), 2.77(t, 2H), 3.25(t, 2H), 4.28(s, 2H), 4.34(s, 2H, NH 2 ), 5.96(s, 1H), 6.64(s, 1H), 7.56(d, 2H ), 7.71(d, 2H), 8.47(s, 1H, NHCO).

类似地由通式XXV的相应的各种6-硝基二氢吲哚分两步制备如下化合物，采用实施例3所述的方法用合适的醛还原烷基化，随后按照上述的方法用锌粉还原。The following compounds were similarly prepared in two steps from the corresponding 6-nitroindolines of general formula XXV by reductive alkylation with the appropriate aldehyde as described in Example 3, followed by zinc as described above powder recovery.

4c N-[6-氨基-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2，2-4c N-[6-amino-1-(5-chlorothien-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2,2- 二甲基丙酰胺Dimethylpropionamide

LC/MS(m/z)364.2([M+1]+)；RT＝2.19，(UV，ELSD)98％，99％.1H NMR(DMSO-d6)：1.20(s，9H)，2.72(t，2H)，3.21(t，2H)，4.33(s，2H)，4.39(br.s，2H，NH2)，6.07(s，1H)，6.64(s，1H)，6.91(d，1H)，6.98(d，1H)，8.48(s，1H，NHCO).LC/MS (m/z) 364.2 ([M+1] + ); RT=2.19, (UV, ELSD) 98%, 99%. 1 H NMR (DMSO-d 6 ): 1.20 (s, 9H), 2.72(t, 2H), 3.21(t, 2H), 4.33(s, 2H), 4.39(br.s, 2H, NH 2 ), 6.07(s, 1H), 6.64(s, 1H), 6.91(d , 1H), 6.98(d, 1H), 8.48(s, 1H, NHCO).

4d N-[6-氨基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟4d N-[6-amino-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluoro 苯基)-乙酰胺Phenyl)-acetamide

LC/MS(m/z)444.0([M+1]+)；RT＝2.65，(UV，ELSD)95％，99％.1H NMR(DMSO-d6)：2.76(t，2H)，3.24(t，2H)，3.57(s，2H)，4.26(s，2H)，4.51(br.s，2H，NH2)，5.92(s，1H)，6.73(s，1H)，7.14(t，2H)，7.36(dd，2H)，7.55(d，2H)，7.71(dd，2H)，9.08(s，1H，NHCO).LC/MS (m/z) 444.0 ([M+1] + ); RT=2.65, (UV, ELSD) 95%, 99%. 1 H NMR (DMSO-d 6 ): 2.76 (t, 2H), 3.24(t, 2H), 3.57(s, 2H), 4.26(s, 2H), 4.51(br.s, 2H, NH 2 ), 5.92(s, 1H), 6.73(s, 1H), 7.14(t , 2H), 7.36(dd, 2H), 7.55(d, 2H), 7.71(dd, 2H), 9.08(s, 1H, NHCO).

4e N-[6-氨基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二4e N-[6-amino-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-di 甲基丁酰胺Methylbutanamide

LC/MS(m/z)406.0([M+1]+)；RT＝2.58，(UV，ELSD)97.4％，99.0％.1H NMR(DMSO-d6)：1.02(s，9H)；2.12(s，2H)；2.78(t，2H)；3.24(t，2H)；4.28(s，2H)，4.48(s，2H，NH2)；5.93(s，1H)；6.74(s，1H)；7.56(d，2H)；7.71(d，2H)；8.81(s，1H，NH).LC/MS (m/z) 406.0 ([M+1] + ); RT=2.58, (UV, ELSD) 97.4%, 99.0%. 1 H NMR (DMSO-d 6 ): 1.02 (s, 9H); 2.12(s, 2H); 2.78(t, 2H); 3.24(t, 2H); 4.28(s, 2H), 4.48(s, 2H, NH 2 ); 5.93(s, 1H); 6.74(s, 1H ); 7.56(d, 2H); 7.71(d, 2H); 8.81(s, 1H, NH).

4f N-[6-氨基-1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁4f N-[6-amino-1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyl 酰胺Amide

LC/MS(m/z)356.0([M+1]+)；RT＝2.26，(UV，ELSD)96.7％，98.9％.1H NMR(DMSO-d6)：1.02(s，9H)；2.13(s，2H)；2.73(t，2H)；3.18(t，2H)；4.16(s，2H)，4.48(s，2H，NH2)；5.98(s，1H)；6.71(s，1H)；7.17(t，2H)；7.36(dd，2H)；8.80(s，1H，NH).LC/MS (m/z) 356.0 ([M+1] + ); RT=2.26, (UV, ELSD) 96.7%, 98.9%. 1 H NMR (DMSO-d 6 ): 1.02 (s, 9H); 2.13(s, 2H); 2.73(t, 2H); 3.18(t, 2H); 4.16(s, 2H), 4.48(s, 2H, NH 2 ); 5.98(s, 1H); 6.71(s, 1H ); 7.17(t, 2H); 7.36(dd, 2H); 8.80(s, 1H, NH).

4g N-[6-氨基-1-(3-氟-4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-4g N-[6-amino-1-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]- 3，3-二甲基丁酰胺3,3-Dimethylbutanamide

LC/MS(m/z)424.0([M+1]+)；RT＝2.58，(UV，ELSD)92.0％，98.8％.1H NMR(DMSO-d6)：1.01(s，9H)；2.12(s，2H)；2.79(t，2H)；3.28(t，2H)；4.27(s，2H)，4.48(s，2H，NH2)；5.90(s，1H)；6.75(s，1H)；7.39(d，1H)；7.45(d，1H)；7.78(t，1H)；8.80(s，1H，NH).LC/MS (m/z) 424.0 ([M+1] + ); RT=2.58, (UV, ELSD) 92.0%, 98.8%. 1 H NMR (DMSO-d 6 ): 1.01 (s, 9H); 2.12(s, 2H); 2.79(t, 2H); 3.28(t, 2H); 4.27(s, 2H), 4.48(s, 2H, NH 2 ); 5.90(s, 1H); 6.75(s, 1H ); 7.39(d, 1H); 7.45(d, 1H); 7.78(t, 1H); 8.80(s, 1H, NH).

                         实施例5Example 5

5a N-[1-(5-氯噻吩-2-基甲基)-1H-吲哚-5-基]-3，3-二甲基丁酰胺5a N-[1-(5-chlorothiophen-2-ylmethyl)-1H-indol-5-yl]-3,3-dimethylbutanamide

往N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺(20mg)的二甲亚砜-d6(0.6ml)溶液中加入2，3，5，6-四氯[1，4]苯醌(65mg)。在70℃下将得到的混合物加热5分钟，让其冷却，倾入NaHSO3(1g)的水(5ml)溶液中，随后加入25％的氨水(5ml)和10％的NaOH水溶液(5ml)。用CH2Cl2(3×10ml)萃取该混合物，用水和1M HCl洗涤该合并的有机溶液，经SiO2(10g)柱塞过滤，并用乙酸乙酯/庚烷(1∶1)洗脱。蒸发后的粗产物通过制备型LC/MS纯化，得到无色固体状的标题化合物5mg。To N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide (20mg) 2,3,5,6-Tetrachloro[1,4]benzoquinone (65 mg) was added to the solution of methyl sulfoxide-d 6 (0.6 ml). The resulting mixture was heated at 70° C. for 5 minutes, allowed to cool, and poured into a solution of NaHSO 3 (1 g) in water (5 ml), followed by the addition of 25% ammonia (5 ml) and 10% aqueous NaOH (5 ml). The mixture was extracted with CH2Cl2 (3 x 10 ml), the combined organic solution was washed with water and 1M HCl, filtered through a plug of SiO2 (10 g) and eluted with ethyl acetate/heptane (1: 1 ). The crude product after evaporation was purified by preparative LC/MS to afford 5 mg of the title compound as a colorless solid.

LC/MS(m/z)361.1([M+1]+)；RT＝3.43，(UV，ELSD)96％，99％.1H NMR (DMSO-d6)：1.03(s，9H)，2.16(s，2H)，5.51(s，2H)，6.41(d，1H)，6.95(d，1H)，6.98(d，1H)，7.21(dd，1H)，7.41(d，1H)，7.44(d，1H)，7.87(d，1H)，9.60(s，1H，NHCO).LC/MS (m/z) 361.1 ([M+1] + ); RT=3.43, (UV, ELSD) 96%, 99%. 1 H NMR (DMSO-d 6 ): 1.03 (s, 9H), 2.16(s, 2H), 5.51(s, 2H), 6.41(d, 1H), 6.95(d, 1H), 6.98(d, 1H), 7.21(dd, 1H), 7.41(d, 1H), 7.44 (d, 1H), 7.87(d, 1H), 9.60(s, 1H, NHCO).

                         实施例6Example 6

6a N-[6-溴-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲6a N-[6-bromo-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethyl 基丁酰胺butyramide

按照实施例1中所述方法，由3，3-二甲基-N-(6-溴-2，3-二氢-1H-吲哚-5-基)-丁酰胺(25mg)和4-三氟甲基苯甲醛(64mg)制备得到标题化合物16.7mg。LC/MS(m/z)469.1([M+1]+)；RT＝3.99，(UV，ELSD)97.4％，95.1％。According to the method described in Example 1, from 3,3-dimethyl-N-(6-bromo-2,3-dihydro-1H-indol-5-yl)-butanamide (25 mg) and 4- Trifluoromethylbenzaldehyde (64 mg) was prepared to give 16.7 mg of the title compound. LC/MS (m/z) 469.1 ([M+1] + ); RT = 3.99, (UV, ELSD) 97.4%, 95.1%.

类似地使用合适的醛制备如下化合物：The following compounds were prepared similarly using the appropriate aldehyde:

6b N-[6-溴-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二6b N-[6-bromo-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-di 甲基丁酰胺Methylbutanamide

得到标题化合物16.8mg。LC/MS(m/z)443.1([M+1]+)；RT＝3.92，(UV，ELSD)96.3％，94.9％。16.8 mg of the title compound were obtained. LC/MS (m/z) 443.1 ([M+1] + ); RT = 3.92, (UV, ELSD) 96.3%, 94.9%.

                         实施例7Example 7

通用方法：往乙醛(25mg或0.025ml)和合适的二氢吲哚(7mg)在甲醇(0.5ml)中的混合物中加入NaBH3CN(20mg)的甲醇(0.2ml)溶液，随后加入乙酸(0.05ml)。将得到的溶液或悬浮液超声处理5分钟并在50℃下保温60分钟，随后在真空中蒸发。将残余物溶解于DMSO(2.5ml)和水(100ml)中。通过制备型LC/MS分离产物。General procedure: To a mixture of acetaldehyde (25mg or 0.025ml) and the appropriate indoline (7mg) in methanol (0.5ml) was added NaBH3CN (20mg) in methanol (0.2ml) followed by acetic acid (0.05ml). The resulting solution or suspension was sonicated for 5 minutes and incubated at 50°C for 60 minutes, then evaporated in vacuo. The residue was dissolved in DMSO (2.5ml) and water (100ml). The product was isolated by preparative LC/MS.

由N-(2，3-二氢-1H-吲哚-5-基)-3，3-二甲基-丁酰胺(7a-7z化合物)或N-(2，3-二氢-1H-吲哚-5-基)-2-(4-氟苯基)-乙酰胺(7aa-7aw化合物)和合适的醛(参见下表2)制备如下化合物：From N-(2,3-dihydro-1H-indol-5-yl)-3,3-dimethyl-butanamide (7a-7z compound) or N-(2,3-dihydro-1H- Indol-5-yl)-2-(4-fluorophenyl)-acetamide (7aa-7aw compounds) and the appropriate aldehyde (see Table 2 below) to prepare the following compounds:

7a N-[1-(4-氯苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺7a N-[1-(4-chlorobenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide

LC/MS(m/z)357.2([M+1]+)；RT＝3.17，(UV，ELSD)77.1％，97.2％。LC/MS (m/z) 357.2 ([M+1] + ); RT = 3.17, (UV, ELSD) 77.1%, 97.2%.

7b 3，3-二甲基-N-[1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-丁7b 3,3-Dimethyl-N-[1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-butan 酰胺Amide

LC/MS(m/z)391.4([M+1]+)；RT＝3.44，(UV，ELSD)91.8％，99.6％。LC/MS (m/z) 391.4 ([M+1] + ); RT = 3.44, (UV, ELSD) 91.8%, 99.6%.

7c N-[1-(4-异丙基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰7c N-[1-(4-isopropylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyryl 胺amine

LC/MS(m/z)365.4([M+1]+)；RT＝3.13，(UV，ELSD)89.4％，99.2％。LC/MS (m/z) 365.4 ([M+1] + ); RT = 3.13, (UV, ELSD) 89.4%, 99.2%.

7d N-[1-(3-氟-4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲7d N-[1-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethyl 基丁酰胺butyramide

LC/MS(m/z)409.2([M+1]+)；RT＝3.60，(UV，ELSD)69.6％，98.2％。LC/MS (m/z) 409.2 ([M+1] + ); RT = 3.60, (UV, ELSD) 69.6%, 98.2%.

7e N-[1-(6-氯苯并[1，3]二氧杂环戊烯-5-基甲基)-2，3-二氢-1H-吲哚7e N-[1-(6-chlorobenzo[1,3]dioxol-5-ylmethyl)-2,3-dihydro-1H-indole -5-基]-3，3-二甲基丁酰胺-5-yl]-3,3-dimethylbutanamide

LC/MS(m/z)401.0([M+1]+)；RT＝3.22，(UV，ELSD)94.6％，99.5％。LC/MS (m/z) 401.0 ([M+1] + ); RT = 3.22, (UV, ELSD) 94.6%, 99.5%.

7f N-[1-(3，5-二甲基-1-苯基-1H-吡唑-4-基甲基)-2，3-二氢-1H-吲哚7f N-[1-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-2,3-dihydro-1H-indole -5-基]-3，3-二甲基丁酰胺-5-yl]-3,3-dimethylbutanamide

LC/MS(m/z)417.2([M+1]+)；RT＝2.23，(UV，ELSD)93.3％，98.9％。LC/MS (m/z) 417.2 ([M+1] + ); RT = 2.23, (UV, ELSD) 93.3%, 98.9%.

7g N-[1-(2-氯-5-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲7g N-[1-(2-chloro-5-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethyl 基丁酰胺butyramide

LC/MS(m/z)425.2([M+1]+)；RT＝3.79，(UV，ELSD)75.4％，98.4％。LC/MS (m/z) 425.2 ([M+1] + ); RT = 3.79, (UV, ELSD) 75.4%, 98.4%.

7h N-{1-[5-(4-氯苯氧基)-1，3-二甲基-1H-吡唑-4-基甲基]-2，3-二氢7h N-{1-[5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazol-4-ylmethyl]-2,3-dihydro -1H-吲哚-5-基}-3，3-二甲基丁酰胺-1H-indol-5-yl}-3,3-dimethylbutanamide

LC/MS(m/z)467.3([M+1]+)；RT＝2.71，(UV，ELSD)95.2％，99.8％。LC/MS (m/z) 467.3 ([M+1] + ); RT = 2.71, (UV, ELSD) 95.2%, 99.8%.

7j 3，3-二甲基-N-[1-(6-对甲苯氧基-吡啶-3-基甲基)-2，3-二氢-1H-7j 3,3-Dimethyl-N-[1-(6-p-methylphenoxy-pyridin-3-ylmethyl)-2,3-dihydro-1H- 吲哚-5-基]-丁酰胺Indol-5-yl]-butanamide

LC/MS(m/z)430.2([M+1]+)；RT＝3.15，(UV，ELSD)76.6％，97.9％。LC/MS (m/z) 430.2 ([M+1] + ); RT = 3.15, (UV, ELSD) 76.6%, 97.9%.

7k N-{1-[6-(4-氯苯基硫基)-吡啶-3-基甲基]-2，3-二氢-1H-吲哚-5-7k N-{1-[6-(4-chlorophenylsulfanyl)-pyridin-3-ylmethyl]-2,3-dihydro-1H-indole-5- 基}-3，3-二甲基丁酰胺base}-3,3-dimethylbutyramide

LC/MS(m/z)466.0([M+1]+)；RT＝3.45，(UV，ELSD)69.3％，97.1％。LC/MS (m/z) 466.0 ([M+1] + ); RT = 3.45, (UV, ELSD) 69.3%, 97.1%.

7l N-{1-[6-(4-氰基苯氧基)-吡啶-3-基甲基]-2，3-二氢-1H-吲哚-5-7l N-{1-[6-(4-cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-1H-indole-5- 基}-3，3-二甲基丁酰胺base}-3,3-dimethylbutyramide

LC/MS(m/z)441.4([M+1]+)；RT＝2.98，(UV，ELSD)79.8％，98.9％。LC/MS (m/z) 441.4 ([M+1] + ); RT = 2.98, (UV, ELSD) 79.8%, 98.9%.

7m 3，3-二甲基-N-[1-(6-三氟甲基吡啶-3-基甲基)-2，3-二氢-1H-吲7m 3,3-Dimethyl-N-[1-(6-trifluoromethylpyridin-3-ylmethyl)-2,3-dihydro-1H-ind 哚-5-基]-丁酰胺Indol-5-yl]-butyramide

LC/MS(m/z)392.4([M+1]+)；RT＝3.10，(UV，ELSD)82.5％，99.5％。LC/MS (m/z) 392.4 ([M+1] + ); RT = 3.10, (UV, ELSD) 82.5%, 99.5%.

7p 3，3-二甲基-N-[1-(3-甲基-苯并[b]噻吩-2-基甲基)-2，3-二氢-1H-7p 3,3-Dimethyl-N-[1-(3-methyl-benzo[b]thiophen-2-ylmethyl)-2,3-dihydro-1H- 吲哚-5-基]-丁酰胺Indol-5-yl]-butanamide

LC/MS(m/z)393.3([M+1]+)；RT＝3.56，(UV，ELSD)72.8％，97.9％。LC/MS (m/z) 393.3 ([M+1] + ); RT = 3.56, (UV, ELSD) 72.8%, 97.9%.

7q N-[1-(6-氟-4H-苯并[1，3]二氧杂环己烯-8-基甲基)-2，3-二氢-1H-7q N-[1-(6-fluoro-4H-benzo[1,3]dioxin-8-ylmethyl)-2,3-dihydro-1H- 吲哚-5-基]-3，3-二甲基丁酰胺Indol-5-yl]-3,3-dimethylbutanamide

LC/MS(m/z)399.2([M+1]+)；RT＝2.75，(UV，ELSD)84.9％，99.3％。LC/MS (m/z) 399.2 ([M+1] + ); RT = 2.75, (UV, ELSD) 84.9%, 99.3%.

7s 3，3-二甲基-N-[1-(6-苯氧基吡啶-3-基甲基)-2，3-二氢-1H-吲哚-7s 3,3-Dimethyl-N-[1-(6-phenoxypyridin-3-ylmethyl)-2,3-dihydro-1H-indole- 5-基]-丁酰胺5-yl]-butanamide

LC/MS(m/z)416.2([M+1]+)；RT＝2.98，(UV，ELSD)67.5％，96.5％。LC/MS (m/z) 416.2 ([M+1] + ); RT = 2.98, (UV, ELSD) 67.5%, 96.5%.

7u 3，3-二甲基-N-[1-(3-甲基-5-苯基-异噁唑-4-基甲基)-2，3-二氢-7u 3,3-Dimethyl-N-[1-(3-methyl-5-phenyl-isoxazol-4-ylmethyl)-2,3-dihydro- 1H-吲哚-5-基]-丁酰胺1H-Indol-5-yl]-butanamide

LC/MS(m/z)404.4([M+1]+)；RT＝3.24，(UV，ELSD)97.6％，99.9％。LC/MS (m/z) 404.4 ([M+1] + ); RT = 3.24, (UV, ELSD) 97.6%, 99.9%.

7v N-(1-苯并[b]噻吩-2-基甲基-2，3-二氢-1H-吲哚-5-基)-3，3-二甲7v N-(1-benzo[b]thiophen-2-ylmethyl-2,3-dihydro-1H-indol-5-yl)-3,3-dimethyl 基丁酰胺butyramide

LC/MS(m/z)379.3([M+1]+)；RT＝3.44，(UV，ELSD)71.8％，97.6％。LC/MS (m/z) 379.3 ([M+1] + ); RT = 3.44, (UV, ELSD) 71.8%, 97.6%.

7w N-{1-[1-(4-氟苯基)-5-甲基-1H-吡唑-4-基甲基]-2，3-二氢-1H-7w N-{1-[1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-ylmethyl]-2,3-dihydro-1H- 吲哚-5-基}-3，3-二甲基丁酰胺Indol-5-yl}-3,3-dimethylbutanamide

LC/MS(m/z)421.4([M+1]+)；RT＝2.24，(UV，ELSD)79.5％，98.9％。LC/MS (m/z) 421.4 ([M+1] + ); RT = 2.24, (UV, ELSD) 79.5%, 98.9%.

7y 3，3-二甲基-N-[1-(5-甲基噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-7y 3,3-Dimethyl-N-[1-(5-methylthiophen-2-ylmethyl)-2,3-dihydro-1H-indole-5- 基]-丁酰胺base]-butyramide

LC/MS(m/z)343.1([M+1]+)；RT＝2.84，(UV，ELSD)59.9％，89.1％。LC/MS (m/z) 343.1 ([M+1] + ); RT = 2.84, (UV, ELSD) 59.9%, 89.1%.

7z 3，3-二甲基-N-[1-(4-吡咯-1-基-苄基)-2，3-二氢-1H-吲哚-5-基]-7z 3,3-Dimethyl-N-[1-(4-pyrrol-1-yl-benzyl)-2,3-dihydro-1H-indol-5-yl]- 丁酰胺Butanamide

LC/MS(m/z)388.3([M+1]+)；RT＝3.03，(UV，ELSD)81.1％，99.5％。LC/MS (m/z) 388.3 ([M+1] + ); RT = 3.03, (UV, ELSD) 81.1%, 99.5%.

7aa N-[1-(4-氯苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺7aa N-[1-(4-chlorobenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide

LC/MS(m/z)395.1([M+1]+)；RT＝2.99，(UV，ELSD)93.4％，93.1％。LC/MS (m/z) 395.1 ([M+1] + ); RT = 2.99, (UV, ELSD) 93.4%, 93.1%.

7ab 2-(4-氟苯基)-N-[1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-7ab 2-(4-fluorophenyl)-N-[1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]- 乙酰胺Acetamide

LC/MS(m/z)429.1([M+1]+)；RT＝3.24，(UV，ELSD)76.6％，87.4％。LC/MS (m/z) 429.1 ([M+1] + ); RT = 3.24, (UV, ELSD) 76.6%, 87.4%.

7ac 2-(4-氟苯基)-N-[1-(4-异丙基苄基)-2，3-二氢-1H-吲哚-5-基]-乙7ac 2-(4-fluorophenyl)-N-[1-(4-isopropylbenzyl)-2,3-dihydro-1H-indol-5-yl]-ethyl 酰胺Amide

LC/MS(m/z)403.1([M+1]+)；RT＝2.96，(UV，ELSD)91.5％，83.7％。LC/MS (m/z) 403.1 ([M+1] + ); RT = 2.96, (UV, ELSD) 91.5%, 83.7%.

7ad 2-(4-氟苯基)-N-[1-(3-氟-4-三氟甲基苄基)-2，3-二氢-1H-吲哚-7ad 2-(4-fluorophenyl)-N-[1-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-1H-indole- 5-基]-乙酰胺5-yl]-acetamide

LC/MS(m/z)447.2([M+1]+)；RT＝3.36，(UV，ELSD)79.3％，90.4％。LC/MS (m/z) 447.2 ([M+1] + ); RT = 3.36, (UV, ELSD) 79.3%, 90.4%.

7ae N-[1-(6-氯苯并[1，3]二氧杂环戊烯-5-基甲基)-2，3-二氢-1H-吲7ae N-[1-(6-chlorobenzo[1,3]dioxol-5-ylmethyl)-2,3-dihydro-1H-ind 哚-5-基]-2-(4-氟苯基)-乙酰胺Indol-5-yl]-2-(4-fluorophenyl)-acetamide

LC/MS(m/z)439.0([M+1]+)；RT＝3.02，(UV，ELSD)94.0％，92.2％。LC/MS (m/z) 439.0 ([M+1] + ); RT = 3.02, (UV, ELSD) 94.0%, 92.2%.

7af N-[1-(3，5-二甲基-1-苯基-1H-吡唑-4-基甲基)-2，3-二氢-1H-吲7af N-[1-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-2,3-dihydro-1H-ind 哚-5-基]-2-(4-氟苯基)-乙酰胺Indol-5-yl]-2-(4-fluorophenyl)-acetamide

LC/MS(m/z)455.0([M+1]+)；RT＝2.14，(UV，ELSD)97.1％，91.4％。LC/MS (m/z) 455.0 ([M+1] + ); RT = 2.14, (UV, ELSD) 97.1%, 91.4%.

7ag N-[1-(2-氯-5-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟7ag N-[1-(2-chloro-5-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluoro 苯基)-乙酰胺Phenyl)-acetamide

LC/MS(m/z)463.1([M+1]+)；RT＝3.53，(UV，ELSD)98.3％，95.3％。LC/MS (m/z) 463.1 ([M+1] + ); RT = 3.53, (UV, ELSD) 98.3%, 95.3%.

7ah N-{1-[5-(4-氯苯氧基)-1，3-二甲基-1H-吡唑-4-基甲基]-2，3-二7ah N-{1-[5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazol-4-ylmethyl]-2,3-di 氢-1H-吲哚-5-基}-2-(4-氟苯基)-乙酰胺Hydrogen-1H-indol-5-yl}-2-(4-fluorophenyl)-acetamide

LC/MS(m/z)503.3([M-1]+)；RT＝2.55，(UV，ELSD)92.3％，90.5％。LC/MS (m/z) 503.3 ([M-1] + ); RT = 2.55, (UV, ELSD) 92.3%, 90.5%.

7ai N-{1-[6-(4-氰基苯氧基)-吡啶-3-基甲基]-2，3-二氢-1H-吲哚-5-7ai N-{1-[6-(4-cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-1H-indole-5- 基}-2-(4-氟苯基)-乙酰胺Base}-2-(4-fluorophenyl)-acetamide

LC/MS(m/z)479.1([M+1]+)；RT＝2.81，(UV，ELSD)84.1％，87.1％。LC/MS (m/z) 479.1 ([M+1] + ); RT = 2.81, (UV, ELSD) 84.1%, 87.1%.

7al 2-(4-氟苯基)-N-[1-(3-甲基-苯并[b]噻吩-2-基甲基)-2，3-二氢-7al 2-(4-fluorophenyl)-N-[1-(3-methyl-benzo[b]thiophen-2-ylmethyl)-2,3-dihydro- 1H-吲哚-5-基]-乙酰胺1H-Indol-5-yl]-acetamide

LC/MS(m/z)431.2([M+1]+)；RT＝3.34，(UV，ELSD)60.2％，88.8％。LC/MS (m/z) 431.2 ([M+1] + ); RT = 3.34, (UV, ELSD) 60.2%, 88.8%.

7am N-[1-(6-氟-4H-苯并[1，3]二氧杂环己烯-8-基甲基)-2，3-二氢-7am N-[1-(6-fluoro-4H-benzo[1,3]dioxin-8-ylmethyl)-2,3-dihydro- 1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺1H-Indol-5-yl]-2-(4-fluorophenyl)-acetamide

LC/MS(m/z)437.0([M+1]+)；RT＝2.62，(UV，ELSD)79.7％，83.6％。LC/MS (m/z) 437.0 ([M+1] + ); RT = 2.62, (UV, ELSD) 79.7%, 83.6%.

7ao 2-(4-氟苯基)-N-[1-(6-苯氧基吡啶-3-基甲基)-2，3-二氢-1H-吲7ao 2-(4-fluorophenyl)-N-[1-(6-phenoxypyridin-3-ylmethyl)-2,3-dihydro-1H-ind 哚-5-基]-乙酰胺Indol-5-yl]-acetamide

LC/MS(m/z)454.3([M+1]+)；RT＝2.81，(UV，ELSD)77.9％，83.1％。LC/MS (m/z) 454.3 ([M+1] + ); RT = 2.81, (UV, ELSD) 77.9%, 83.1%.

7ar N-(1-苯并[b]噻吩-2-基甲基-2，3-二氢-1H-吲哚-5-基)-2-(4-氟苯7ar N-(1-benzo[b]thiophen-2-ylmethyl-2,3-dihydro-1H-indol-5-yl)-2-(4-fluorobenzene 基)-乙酰胺base)-acetamide

LC/MS(m/z)417.2([M+1]+)；RT＝3.22，(UV，ELSD)80.2％，89.4％。LC/MS (m/z) 417.2 ([M+1] + ); RT = 3.22, (UV, ELSD) 80.2%, 89.4%.

7as 2-(4-氟苯基)-N-{1-[1-(4-氟苯基)-5-甲基-1H-吡唑-4-基甲基]-7as 2-(4-fluorophenyl)-N-{1-[1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-ylmethyl]- 2，3-二氢-1H-吲哚-5-基}-乙酰胺2,3-Dihydro-1H-indol-5-yl}-acetamide

LC/MS(m/z)459.3([M+1]+)；RT＝2.15，(UV，ELSD)91.5％，88.7％。LC/MS (m/z) 459.3 ([M+1] + ); RT = 2.15, (UV, ELSD) 91.5%, 88.7%.

7au 2-(4-氟苯基)-N-[1-(5-甲基噻吩-2-基甲基)-2，3-二氢-1H-吲哚-7au 2-(4-fluorophenyl)-N-[1-(5-methylthiophen-2-ylmethyl)-2,3-dihydro-1H-indole- 5-基]-乙酰胺5-yl]-acetamide

LC/MS(m/z)381.1([M+1]+)；RT＝2.71，(UV，ELSD)76.6％，82.9％。LC/MS (m/z) 381.1 ([M+1] + ); RT = 2.71, (UV, ELSD) 76.6%, 82.9%.

7av 2-(4-氟苯基)-N-[1-(4-吡咯-1-基-苄基)-2，3-二氢-1H-吲哚-5-7av 2-(4-fluorophenyl)-N-[1-(4-pyrrol-1-yl-benzyl)-2,3-dihydro-1H-indole-5- 基]-乙酰胺base]-acetamide

LC/MS(m/z)426.1([M+1]+)；RT＝2.87，(UV，ELSD)92.2％，88.2％。LC/MS (m/z) 426.1 ([M+1] + ); RT = 2.87, (UV, ELSD) 92.2%, 88.2%.

表2.在本发明7a-7av的化合物制备中使用的醛   本发明的化合物 醛 分子量 厂商 目录号   7a   4-氯苯甲醛   140.568   Aldrich   7b   4-(三氟甲基)-苯甲醛   174.12   Aldrich   7c   4-异丙基苯甲醛   148.204   Aldrich   7d   3-氟-4-(三氟甲基)苯甲醛   192.111   ABCR   AV20008   7e   6-氯胡椒醛   184.577   ABCR   AV13607   7f   3，5-二甲基-1-苯基吡唑-4-甲醛   200.24   Acros Organics   40852-0050   7g   2-氯-5-(三氟甲基)苯甲醛   208.566   Aldrich   37，682-5 7h   5-(4-氯苯氧基)-1，3-二甲基-1H-吡唑-4-甲醛 250.684 Bionet Research 11F-431S   7j   6-(4-甲基苯氧基)烟碱醛   213.235   Bionet Research   5L-355S   7k   6-[(4-氯苯基)硫基]烟碱醛   249.72   Bionet Research   5L-356S   7l   4-[(5-甲酰基-2-吡啶基)氧基]苯甲腈   224.218   Bionet Research   6L-309S   7m   6-(三氟甲基)吡啶-3-甲醛   175.109   Fluorochem   9397   7p   3-甲基苯并[b]噻吩-2-甲醛   176.238   ABCR   AV11375   7q   5-氟-4H-1，3-苯并二氧杂环己烯-5-甲醛   182.149   Maybridge   CC 01904   7s   6-苯氧基烟碱醛   199.208   Maybridge   CC 19604   7u   3-甲基-5-苯基-4-异噁唑甲醛   187.197   Maybridge   CC 20304   7v   1-苯并噻吩-2-甲醛   162.211   Specs   942/25034639   7w   1-(4-氟苯基)-5-甲基-1H-吡唑-4-甲醛   204.203   Maybridge   MO 00310   7y   5-甲基-2-噻吩甲醛   126.178   Aldrich   M8，441-0   7z   4-(1H-吡咯-1-基)苯甲醛   171.198   Maybridge   N/A   7aa   4-氯苯甲醛   140.568   Aldrich   7ab   4-(三氟甲基)苯甲醛   174.12   Aldrich   7ac   4-异丙基苯甲醛   148.204   Aldrich   7ad   3-氟-4-(三氟甲基)苯甲醛   192.111   ABCR   AV20008   7ae   6-氯胡椒醛   184.577   ABCR   AV13607   7af   3，5-二甲基-1-苯基吡唑-4-甲醛   200.24   Acros Organics   40852-0050   7ag   2-氯-5-(三氟甲基)苯甲醛   208.566   Aldrich   37，682-5 7ah   5-(4-氯苯氧基)-1，3-二甲基-1H-吡唑-4-甲醛 250.684 Bionet Research 11F-431S   7ai   4-[(5-甲酰基-2-吡啶基)氧基]苯甲腈   224.218   Bionet Research   6L-309S Table 2. Aldehydes Used in the Preparation of Compounds of the Invention 7a-7av Compounds of the invention aldehyde molecular weight manufacturers catalog number 7a 4-Chlorobenzaldehyde 140.568 Aldrich 7b 4-(Trifluoromethyl)-benzaldehyde 174.12 Aldrich 7c 4-Isopropylbenzaldehyde 148.204 Aldrich 7d 3-fluoro-4-(trifluoromethyl)benzaldehyde 192.111 ABCR AV20008 7e 6-chloropiperonal 184.577 ABCR AV13607 7f 3,5-Dimethyl-1-phenylpyrazole-4-carbaldehyde 200.24 Acros Organics 40852-0050 7g 2-Chloro-5-(trifluoromethyl)benzaldehyde 208.566 Aldrich 37,682-5 7h 5-(4-Chlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde 250.684 Bionet Research 11F-431S 7j 6-(4-Methylphenoxy)nicotinaldehyde 213.235 Bionet Research 5L-355S 7k 6-[(4-Chlorophenyl)thio]nicotinaldehyde 249.72 Bionet Research 5L-356S 7l 4-[(5-Formyl-2-pyridyl)oxy]benzonitrile 224.218 Bionet Research 6L-309S 7m 6-(Trifluoromethyl)pyridine-3-carbaldehyde 175.109 Fluorochem 9397 7p 3-Methylbenzo[b]thiophene-2-carbaldehyde 176.238 ABCR AV11375 7q 5-fluoro-4H-1,3-benzodioxine-5-carbaldehyde 182.149 Maybridge CC 01904 7s 6-Phenoxynicotinaldehyde 199.208 Maybridge CC 19604 7u 3-Methyl-5-phenyl-4-isoxazolecarbaldehyde 187.197 Maybridge CC 20304 7v 1-Benzothiophene-2-carbaldehyde 162.211 Specs 942/25034639 7w 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carbaldehyde 204.203 Maybridge MO 00310 7 years 5-Methyl-2-thiophenecarbaldehyde 126.178 Aldrich M8, 441-0 7z 4-(1H-Pyrrol-1-yl)benzaldehyde 171.198 Maybridge N/A 7aa 4-Chlorobenzaldehyde 140.568 Aldrich 7ab 4-(Trifluoromethyl)benzaldehyde 174.12 Aldrich 7ac 4-Isopropylbenzaldehyde 148.204 Aldrich 7ad 3-fluoro-4-(trifluoromethyl)benzaldehyde 192.111 ABCR AV20008 7ae 6-chloropiperonal 184.577 ABCR AV13607 7af 3,5-Dimethyl-1-phenylpyrazole-4-carbaldehyde 200.24 Acros Organics 40852-0050 7ag 2-Chloro-5-(trifluoromethyl)benzaldehyde 208.566 Aldrich 37,682-5 7ah 5-(4-Chlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde 250.684 Bionet Research 11F-431S 7ai 4-[(5-Formyl-2-pyridyl)oxy]benzonitrile 224.218 Bionet Research 6L-309S

  本发明的化合物 Compounds of the invention 醛aldehyde 分子量molecular weight 厂商manufacturers 目录号catalog number   7al 7al   3-甲基苯并[b]噻吩-2-甲醛 3-Methylbenzo[b]thiophene-2-carbaldehyde   176.238 176.238   ABCR ABCR   AV11375 AV11375   7am 7 am   5-氟-4H-1，3-苯并二氧杂环己烯-5-甲醛 5-fluoro-4H-1,3-benzodioxine-5-carbaldehyde   182.149 182.149   Maybridge Maybridge   CC 01904 CC 01904   7ao 7ao   6-苯氧基烟碱醛 6-Phenoxynicotinaldehyde   199.208 199.208   Maybridge Maybridge   CC 19604 CC 19604   7ar 7ar   1-苯并噻吩-2-甲醛 1-Benzothiophene-2-carbaldehyde   162.211 162.211   Specs Specs   942/25034639 942/25034639   7as 7as   1-(4-氟苯基)-5-甲基-1H-吡唑-4-甲醛 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carbaldehyde   204.203 204.203   Maybridge Maybridge   MO 00310 MO 00310   7au 7au   5-甲基-2-噻吩甲醛 5-Methyl-2-thiophenecarbaldehyde   126.178 126.178   Aldrich Aldrich   M8，441-0 M8, 441-0   7av 7av   4-(1H-吡咯-1-基)苯甲醛 4-(1H-pyrrol-1-yl)benzaldehyde   171.198 171.198   Maybridge Maybridge   N/A N/A

                         体外和体内试验In vitro and in vivo tests

本发明的化合物已在一个或多个以下的模型中进行试验并显示出效果：The compounds of the present invention have been tested and shown to be effective in one or more of the following models:

通过KCNQ2通道的相对流量Relative flux through KCNQ2 channels

该例证了用于评估本发明化合物的KCNQ2筛选方案。所述分析测量了经KCNQ2通道的相对流量，按照Tang等(Tang，W.等，J.Biomol.Screen.2001，6，325-331)描述的用于hERG钾通道的方法进行并进行了如下改进。This exemplifies the KCNQ2 screening protocol used to evaluate compounds of the invention. The assay measures the relative flux through the KCNQ2 channel, as described for the hERG potassium channel by Tang et al. Improve.

在试验当天将稳定表达电压门控KCNQ2通道的足够量的CHO细胞平板培养到足够产生单汇合层的密度。在试验前一天将细胞接种并装载1μCi/ml[86Rb]过夜。在试验当天用含HBSS的缓冲液洗涤这些细胞。用药物预培养细胞30分钟，并在药物持续存在下，用15mMKCl的次最大浓度刺激[86Rb+]流量30分钟。经过一段适当的培养时间后，移去上层清液，并在液体闪烁计数器(Tricarb)中计数。用2mMNaOH溶解细胞，并计数86Rb+的量。如下计算相对流量：Sufficient numbers of CHO cells stably expressing voltage-gated KCNQ2 channels were plated on the day of the assay to a density sufficient to generate monoconfluent layers. Cells were plated and loaded with 1 μCi/ml [ 86 Rb] overnight the day before the assay. The cells were washed with HBSS-containing buffer on the day of the experiment. Cells were pre-incubated with drugs for 30 minutes and [ 86 Rb + ] flux was stimulated for 30 minutes with a submaximal concentration of 15 mM KCl in the continued presence of drugs. After an appropriate incubation time, the supernatant was removed and counted in a liquid scintillation counter (Tricarb). Cells were lysed with 2mM NaOH, and the amount of 86 Rb+ was counted. The relative flow is calculated as follows:

((CPMsuper/(CPMsuper+CPMcell))Cmpd/((CPM super /(CPM super +CPM cell ))C mpd /

(CPMsuper/(CPMsuper+CPMcell))15mM KCl)*100-100.(CPM super /(CPM super +CPM cell ))15mM KCl)*100-100.

本发明的化合物的EC50小于20000nM，在大多数情况下小于2000nM，在许多情况下小于200nM。因此，认为本发明的化合物可用于治疗与KCNQ家族钾通道相关的疾病。The compounds of the invention have an EC50 of less than 20000 nM, in most cases less than 2000 nM, in many cases less than 200 nM. Therefore, it is believed that the compounds of the present invention are useful in the treatment of diseases associated with potassium channels of the KCNQ family.

电生理学的膜片钳记录Patch-clamp recordings for electrophysiology

使用传统的膜片钳记录技术(Hamill OP等Pflügers Arch 1981；391：85-100)记录全细胞膜片钳构型的哺乳动物的CHO细胞的电压激活的KCNQ2电流。在正常的细胞培养条件下、在CO2培养箱中培养稳定表达电压激活的KCNQ2电流的CHO细胞并在平板培养1至7天后用于电生理学记录。从-100mV至-40mV的膜静电位(membraneholding potential)以增量为5-20mV(或斜坡刺激方式)逐步提高至+80mV(TatulianL等JNeuroscience2001；21(15)：5535-5545)将KCNQ2钾离子通道活化。以电压活化的KCNQ2电流的各种参数来评价由化合物诱导的电生理学的效果。特别是研究了对电流的活化阈值和对最大诱导的电流的影响。Voltage-activated KCNQ2 currents were recorded from mammalian CHO cells in a whole-cell patch-clamp configuration using conventional patch-clamp recording techniques (Hamill OP et al. Pflügers Arch 1981;391:85-100). CHO cells stably expressing voltage-activated KCNQ2 currents were cultured under normal cell culture conditions in a CO 2 incubator and plated for 1 to 7 days for electrophysiological recordings. The membrane holding potential (membraneholding potential) from -100mV to -40mV is gradually increased to +80mV in increments of 5-20mV (or ramp stimulation mode) (TatulianL et al. JNeuroscience2001; 21 (15): 5535-5545) KCNQ2 potassium ions Channel activation. The electrophysiological effects induced by the compounds were evaluated on various parameters of voltage-activated KCNQ2 currents. In particular the effect on the activation threshold of the current and on the maximum induced current was investigated.

在本试验中测试了本发明的化合物中一些化合物。预期活化阈值的左移(left-ward)或最大诱导钾电流的增加将降低神经网络中的活性，并且因而使得化合物可用于与神经活性增加相关的疾病(如癫痫)Some of the compounds of the invention were tested in this assay. It is expected that a left-ward shift of the activation threshold or an increase in the maximum induced potassium current will reduce the activity in the neural network and thus make the compound useful for diseases associated with increased neural activity (such as epilepsy)

最大电击maximum shock

使用角膜电极(corneal electrode)在各雄性小鼠组上进行该试验，为了诱发具有后肢强直性伸展特征的癫痫，使用26mA的方波电流作用0.4秒(Wlaz等人，Epilepsy Research 1998，30，219-229)。The test was carried out on each group of male mice using corneal electrodes, and in order to induce epilepsy characterized by tonic extension of the hind limbs, a square wave current of 26 mA was applied for 0.4 seconds (Wlaz et al., Epilepsy Research 1998, 30, 219 -229).

毛果芸香碱诱发的癫痫Pilocarpine-induced epilepsy

通过给雄性小鼠组腹膜内注射250mg/kg毛果芸香碱诱发毛果芸香碱诱发的癫痫，并观察30分钟内导致失态的癫痫发作情况。(Starr等人，Pharmacology Biochemistry and Behavior 1993，45，321-325)Pilocarpine-induced epilepsy was induced by intraperitoneally injecting 250 mg/kg pilocarpine into the male mouse group, and the seizures leading to gaffes were observed within 30 minutes. (Starr et al., Pharmacology Biochemistry and Behavior 1993, 45, 321-325)

电癫痫阈值试验Electrical Seizure Threshold Test

使用升高及降低(up-and-down)方法(Kimball等人，RadiationResearch 1957，1-12)的改进方法来测定诱导雄性小鼠组响应角膜电击的后肢强直性伸展的中位阈值。给予各组的第一只小鼠14mA(0.4s，50Hz)的电击，并观察癫痫发作。如果观察到出现癫痫，则将下一只小鼠所用的电流降低1mA，但是如果未观察到出现癫痫，则将电流增加1mA。A modification of the up-and-down method (Kimball et al., Radiation Research 1957, 1-12) was used to determine the median threshold for inducing tonic extension of the hindlimb in groups of male mice in response to corneal shock. The first mouse of each group was given an electric shock of 14 mA (0.4 s, 50 Hz), and observed for seizures. If seizures were observed, the current applied to the next mouse was reduced by 1 mA, but if no seizures were observed, the current was increased by 1 mA.

对于该治疗组的15只小鼠重复该步骤。This step was repeated for the 15 mice in this treatment group.

化学癫痫阈值试验Chemical Seizure Threshold Test

诱发阵挛性惊厥所需的戊四氮的阈值剂量通过定时往雄性小鼠尾侧静脉注入戊四氮来测定(5mg/mL，0.5ml/min)(Nutt等人，J.Pharmacy and Pharmacology 1986，38，697-698)。The threshold dose of pentetrazol required to induce clonic convulsions was determined by timed infusion of pentetrazol into the tail vein of male mice (5 mg/mL, 0.5 ml/min) (Nutt et al., J.Pharmacy and Pharmacology 1986 , 38, 697-698).

杏仁核点燃诱发Amygdala Ignition Induced

对大鼠进行手术，在背外侧的杏仁核内植入三极电极。手术后，让这些动物康复，然后给大鼠组各种剂量的测试化合物或药物载体。每天用初始后放电阈值+25μA刺激，持续3-5周，记录各种情况下的癫痫发作严重程度、癫痫持续时间以及后放电电流的持续时间(Racine.Electroencephalography and Clinical Neurophysiology1972，32，281-294)。Rats were surgically implanted with tripolar electrodes in the dorsolateral amygdala. Following surgery, the animals are allowed to recover and groups of rats are given various doses of the test compound or drug vehicle. Stimulate with the initial afterdischarge threshold + 25μA every day for 3-5 weeks, and record the severity of seizures, duration of epilepsy and duration of afterdischarge current in various situations (Racine. Electroencephalography and Clinical Neurophysiology1972, 32, 281-294 ).

副作用side effect

中枢神经系统副作用通过小鼠停留在旋转棒(rotarod)装置上的时间来测定(Capacio等人，Drug and Chemical Toxicology 1992，15，177-201)；或者通过计算穿过试验笼的红外光的光束数来测定小鼠的活动能力(Watson等人，Neuropharmacology 1997，36，1369-1375)。通过直肠温度计或能测定温度的植入的无线电遥控传感器测定该化合物对动物主体温度的降温行为(Keeney等人，Physiology and Behaviour2001，74，177-184)。Central nervous system side effects are measured by the time the mouse remains on the rotarod apparatus (Capacio et al., Drug and Chemical Toxicology 1992, 15, 177-201); or by counting the beam of infrared light passing through the test cage The mobility of mice was determined by counting (Watson et al., Neuropharmacology 1997, 36, 1369-1375). The cooling behavior of the compounds on the body temperature of animals was measured by a rectal thermometer or an implanted radio-controlled sensor capable of measuring temperature (Keeney et al., Physiology and Behaviour 2001, 74, 177-184).

药动学Pharmacokinetics

所述化合物的药动学性质由经静脉和口服给药予Spraque Dawley大鼠，然后经20小时取血样测定。使用LC/MS/MS测定血浆浓度。The pharmacokinetic properties of the compounds were determined by intravenous and oral administration to Spraque Dawley rats, followed by blood sampling over 20 hours. Plasma concentrations were determined using LC/MS/MS.

Claims (30)

1.一种通式I的取代的吲哚或二氢吲哚衍生物或其盐，1. A substituted indole or indoline derivative of general formula I or a salt thereof,
Figure A2004800110190002C1
Figure A2004800110190002C1
 其中in 虚线表示任选的键；Dashed lines indicate optional bonds; R1和R1’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；或R 1 and R 1' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-C 3-8 -cycloalkane (en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo Substitute-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; or R1和R1’与其连接的碳原子一起形成3至8元饱和或不饱和环，所述环任选包含1或2个杂原子；R 1 and R 1' together with the carbon atoms to which they are attached form a 3 to 8 membered saturated or unsaturated ring, said ring optionally comprising 1 or 2 heteroatoms; s为0或1；s is 0 or 1; U为O、NR11、S、SO2、SO2NR11、CO-O或CO-NR11；其中R11选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；或R2和R11与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子；U is O, NR 11 , S, SO 2 , SO 2 NR 11 , CO-O or CO-NR 11 ; wherein R 11 is selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; or R 2 and R 11 together form a 4 to 8 membered A saturated or unsaturated ring optionally comprising 1, 2 or 3 other heteroatoms; R2选自氢、C1-6-烷(烯/炔)基、C3-8-坏烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、酰基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤素、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、-NO2、NR10R10’-C1-6-烷(烯/炔)基、NR10R10’-C3-8-环烷(烯)基和NR10R10’-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；其中R 2 is selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -bad(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk( En/alkyn)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-C 3-8 -cycloalkane (en)yl-C 1-6 -alk(en/yn)yl, acyl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy -C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halogen, halo-C 1-6 -alk(en/yn)yl, halo-C 3- 8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano, cyano-C 1-6 -alk( En/alkynyl) group, cyano-C 3-8 -cycloalk(en)yl, cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, - NO 2 , NR 10 R 10' -C 1-6 -alk(en/yn)yl, NR 10 R 10' -C 3-8 -cycloalk(en)yl and NR 10 R 10' -C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; where R10和R10’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3- 8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基，或R 10 and R 10' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-C 3-8 -cycloalkane (en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo Substitute-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, or R10和R10’与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子；R 10 and R 10' together with the nitrogen atom to which they are attached form a 4 to 8 membered saturated or unsaturated ring, which ring optionally contains 1, 2 or 3 other heteroatoms; 条件是当R2为NO2、卤素或氰基时，s为0；和with the proviso that when R2 is NO2 , halo or cyano, s is 0; and 条件是当R2为氢原子或酰基且s为1时，U为NR11、O或S；The proviso is that when R 2 is a hydrogen atom or an acyl group and s is 1, U is NR 11 , O or S; 其中基团-(U)s-R2连接在吲哚或二氢吲哚的4或6位；Wherein the group -(U) s -R 2 is connected to the 4 or 6 position of indole or indoline; q为0或1；q is 0 or 1; Z为O或S；Z is O or S; X为CO或SO2；条件是当X为SO2时，q为0；X is CO or SO 2 ; the condition is that when X is SO 2 , q is 0; R3选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、杂环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、C1-6-烷(烯/炔)基-杂环烷(烯)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-杂环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基-C1-6-烷(烯/炔)基-杂环烷(烯)基、C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基氧基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基氧基-C3-8-环烷(烯)基、C1-6-烷(烯/炔)基氧基-杂环烷(烯)基、芳基-氧基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基氧基-羰基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基氧基-羰基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基氧基-羰基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-杂环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、羟基-C1-6-烷(烯/炔)基-杂环烷(烯)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-杂环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、卤代-C1-6-烷(烯/炔)基-杂环烷(烯)基、卤代-C1-6-烷(烯/炔)基-芳基、卤代-C3-8-环烷(烯)基-芳基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基-芳基、卤代-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基-芳基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-杂环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、氰基-C1-6-烷(烯/炔)基-杂环烷(烯)基、酰基-C1-6-烷(烯/炔)基、酰基-C3-8-环烷(烯)基、酰基-杂环烷(烯)基、酰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、酰基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、酰基-C1-6-烷(烯/炔)基-杂环烷(烯)基和-NR12R12’、任选取代的NR12R12’-C1-6-烷(烯/炔)基、任选取代的NR12R12’-C3-8-环烷(烯)基、任选取代的NR12R12’-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；其中R 3 is selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, heterocycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, C 1-6 -alk(en/yn)yl- Heterocycloalk(en)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-heterocycloalk(en)yl ) group, aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl-C 3- 8 -cycloalk(en)yl, aryl-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, C 1-6 -alk(en/yn)yloxy-C 1 -6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yloxy-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl Oxy-C 3-8 -cycloalk(en)yl, C 1-6 -alk(en/yn)yloxy-heterocycloalk(en)yl, aryl-oxy-C 1-6 -alk (en/yn)yl, aryl-C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl Oxy-carbonyl-C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn) Alkynyl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en) /alkynyl) group, hydroxy-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, hydroxy-C 1-6 -alk(en/yn)yl-heterocycloalkane (en)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-heterocycloalk(en)yl, halo- C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en) ) group, halo-C 1-6 -alk(en/yn)yl-heterocycloalkane(en)yl, halo-C 1-6 -alk(en/yn)yl-aryl, halo-C 3-8 -cycloalk(en)yl-aryl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl-aryl, halo-C 1 -6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl-aryl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8- Cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, cyano-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, acyl- C 1-6 -alk(en/yn)yl, acyl-C 3-8 -cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C 3-8 -cycloalk(en)yl -C 1-6 -alk(en/yn)yl, acyl-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, acyl-C 1-6 -alk( En/alkyn)yl-heterocycloalkan(en)yl and -NR 12 R 12' , optionally substituted NR 12 R 12' -C 1-6 -alk(en/yn)yl, optionally substituted NR 12 R 12' -C 3-8 -cycloalk(en)yl, optionally substituted NR 12 R 12' -C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl ;in R12和R12’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3- 8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3- 8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基，或R 12 and R 12' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3- 8 -cycloalk(en)yl, aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en) ) group, hydroxyl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en) /alkynyl), cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, or R12和R12’与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子；R 12 and R 12' together with the nitrogen atom to which they are attached form a 4 to 8 membered saturated or unsaturated ring, which ring optionally contains 1, 2 or 3 other heteroatoms; 条件是当R3为NR12R12’时，q为0；The condition is that when R 3 is NR 12 R 12' , q is 0; 和and Y表示式II、III、IV、V、VI、XXX和XXXI的基团：Y represents a group of formulas II, III, IV, V, VI, XXX and XXXI:
Figure A2004800110190005C1
Figure A2004800110190005C1
 或
Figure A2004800110190005C2
or
Figure A2004800110190005C2
 其中in 直线表示将Y所示的基团与碳原子连接的键；The straight line represents the bond connecting the group represented by Y to the carbon atom; W为O或S；W is O or S; T为N、NH或O；T is N, NH or O; L为N、C或CH；L is N, C or CH; a为0、1、2或3；a is 0, 1, 2 or 3; b为0、1、2、3或4；b is 0, 1, 2, 3 or 4; c为0或1；c is 0 or 1; d为0、1、2或3；d is 0, 1, 2 or 3; e为0、1或2；e is 0, 1 or 2; f为0、1、2、3、4或5；f is 0, 1, 2, 3, 4 or 5; g为0、1、2、3或4；g is 0, 1, 2, 3 or 4; h为0、1、2或3；h is 0, 1, 2 or 3; j为0、1、2或3；条件是当T为氮原子时，j为0、1、2或3；和当T为NH或氧原子时，j为0、1或2；j is 0, 1, 2 or 3; provided that when T is a nitrogen atom, j is 0, 1, 2 or 3; and when T is NH or an oxygen atom, j is 0, 1 or 2; k为0、1、2、3或4；且k is 0, 1, 2, 3 or 4; and R5各自独立地选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-硫基、芳基-氧基、酰基、C1-6-烷(烯/炔)基氧基、C3-8-环烷(烯)基氧基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基氧基、卤素、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、-CO-NR6R6’、氰基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、-NR7R7’、-S-R8和-SO2R8，或两个相邻的R5与其连接的芳基一起形成任选包含一个或两个杂原子的4至8元环；R 5 are each independently selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk (en/yn)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-thio, aryl-oxy, acyl, C 1-6 -alk(en/yn) )yloxy, C 3-8 -cycloalk(en)yloxy, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy, halogen, halo -C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk (en/yn)yl, -CO-NR 6 R 6' , cyano, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl, Cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, -NR 7 R 7' , -SR 8 and -SO 2 R 8 , or two adjacent R together with the aryl to which it is attached forms a 4 to 8 membered ring optionally containing one or two heteroatoms; R6和R6’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基和芳基；R 6 and R 6' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl and aryl; R7和R7’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基和酰基；R 7 and R 7' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl and acyl; 和and R8选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基和-NR9R9’；其中R9和R9’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基和C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；条件是当R8为-NR9R9’时，R5不为-S-R8；R 8 is selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk( En/alkyn) base, aryl and -NR 9 R 9' ; wherein R 9 and R 9' are independently selected from hydrogen, C 1-6 -alk(en/alkyn) group, C 3-8 -cycloalkane ( alken)yl and C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; with the proviso that when R 8 is -NR 9 R 9' , R 5 is not -SR 8 ; 条件是式I化合物不为以下化合物或其盐：Provided that the compound of formula I is not the following compound or a salt thereof: N-[1-(苯基甲基)-1H-吲哚-5-基]-甲磺酰胺；N-[1-(phenylmethyl)-1H-indol-5-yl]-methanesulfonamide; N-[1-[(4-氟苯基)甲基]-1H-吲哚-5-基]-甲磺酰胺；N-[1-[(4-fluorophenyl)methyl]-1H-indol-5-yl]-methanesulfonamide; N-[2，3-二氢-1-(苯基甲基)-1H-吲哚-5-基]-甲磺酰胺；N-[2,3-dihydro-1-(phenylmethyl)-1H-indol-5-yl]-methanesulfonamide; N-[1-(苯基甲基)-1H-吲哚-5-基]-N’-4-喹啉基-脲；N-[1-(phenylmethyl)-1H-indol-5-yl]-N'-4-quinolyl-urea; N-[1-(苯基甲基)-1H-吲哚-5-基]-N’-4-喹啉基-脲；或N-[1-(phenylmethyl)-1H-indol-5-yl]-N'-4-quinolyl-urea; or 1-(1-苄基-5-二氢吲哚基)-3-苯基-脲。1-(1-Benzyl-5-dihydroindolyl)-3-phenyl-urea. 2.权利要求1的化合物，其中R1或R1’中至少一个为氢原子。2. The compound of claim 1, wherein at least one of R1 or R1 ' is a hydrogen atom. 3.权利要求1和2中任一项的化合物，其中R1和R1’均为氢原子。3. The compound according to any one of claims 1 and 2, wherein R 1 and R 1 ' are both hydrogen atoms. 4.权利要求1-3中任一项的化合物，其中s为0。4. The compound of any one of claims 1-3, wherein s is zero. 5.权利要求1-3中任一项的化合物，其中s为1。5. The compound of any one of claims 1-3, wherein s is 1 . 6.权利要求1-5中任一项的化合物，其中R2为氢原子。6. The compound of any one of claims 1-5, wherein R 2 is a hydrogen atom. 7.权利要求1-4中任一项的化合物，其中R2为NO2或卤原子。7. The compound according to any one of claims 1-4, wherein R 2 is NO 2 or a halogen atom. 8.权利要求1-3和5-7中任一项的化合物，其中U为NR11。8. The compound of any one of claims 1-3 and 5-7, wherein U is NR11 . 9.权利要求8的化合物，其中R11为氢原子。9. The compound of claim 8, wherein R 11 is a hydrogen atom. 10.权利要求1-9中任一项的化合物，其中X为CO。10. The compound of any one of claims 1-9, wherein X is CO. 11.权利要求1-9中任一项的化合物，其中X为SO2。11. The compound of any one of claims 1-9, wherein X is SO2 . 12.权利要求1-11中任一项的化合物，其中q为0。12. The compound of any one of claims 1-11, wherein q is zero. 13.权利要求1-11中任一项的化合物，其中q为1。13. The compound of any one of claims 1-11, wherein q is 1 . 14.权利要求13的化合物，其中Z为氧原子。14. The compound of claim 13, wherein Z is an oxygen atom. 15.权利要求1-14中任一项的化合物，其中R3选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-氧基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)氧基-C1-6-烷(烯/炔)基和-NR12R12’；条件是当R3为NR12R12’时，q为0。15. The compound according to any one of claims 1-14, wherein R is selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, aryl, aryl- C 1-6 -alk(en/yn)yl, aryl-oxy-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)oxy-C 1-6 -alk(en/yn)yl and -NR 12 R 12' ; with the proviso that q is 0 when R 3 is NR 12 R 12' . 16.权利要求15的化合物，其中R3为NR12R12’，q为0，R12和R12’独立地选自氢、C1-6-烷(烯/炔)基、芳基和芳基-C1-6-烷(烯/炔)基，或R12和R12’与其连接的氮原子一起形成任选包含1、2或3个其他杂原子的4至8元饱和或不饱和环。16. The compound of claim 15, wherein R 3 is NR 12 R 12' , q is 0, R 12 and R 12' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, aryl and Aryl-C 1-6 -alk(en/yn)yl, or R 12 and R 12' together with the nitrogen atom to which they are attached form a 4 to 8 membered saturated or unsaturated saturated ring. 17.权利要求1-16中任一项的化合物，其中Y为式II、III、V、XXX或XXXI。17. The compound of any one of claims 1-16, wherein Y is formula II, III, V, XXX or XXXI. 18.权利要求1-17中任一项的化合物，其中Y为式II或III且W为硫原子。18. The compound of any one of claims 1-17, wherein Y is formula II or III and W is a sulfur atom. 19.权利要求1-17中任一项的化合物，其中Y为式XXX且T为氮原子或氧原子。19. The compound of any one of claims 1-17, wherein Y is of formula XXX and T is a nitrogen atom or an oxygen atom. 20.权利要求1-17中任一项的化合物，其中Y为式XXXI且L为C或CH。20. The compound of any one of claims 1-17, wherein Y is of formula XXXI and L is C or CH. 21.权利要求1-20中任一项的化合物，其中R5各自独立地选自C1-6-烷(烯/炔)基、芳基、芳基-硫基、芳基-氧基、卤素和卤代C1-6-烷(烯/炔)基，或者两个邻近的R5与其连接的芳基一起形成任选包含一个或两个杂原子的4至8元环。21. The compound of any one of claims 1-20, wherein each R is independently selected from C 1-6 -alk(en/yn)yl, aryl, aryl-thio, aryl-oxyl, Halogen and haloC 1-6 -alk(en/yn)yl, or two adjacent R 5 together with the aryl to which they are attached form a 4 to 8 membered ring optionally containing one or two heteroatoms. 22.权利要求1-21中任一项的化合物，所述化合物选自以下化合物或其药学上可接受的盐：22. The compound of any one of claims 1-21, selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof: 1)N-[4-氯-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；1) N-[4-chloro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide; 2)N-[4-氯-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；2) N-[4-chloro-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide ; 3)[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸丙酯；3) [1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-propyl carbamate; 4)N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-C-苯基-甲磺酰胺；4) N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-C-phenyl-methanesulfonamide; 5)4-氟-N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-苯甲酰胺；5) 4-fluoro-N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-benzamide; 6)N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；6) N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide; 7)N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-2-噻吩-2-基乙酰胺；7) N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-2-thiophen-2-ylacetamide; 8)N-[1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；8) N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; 9)3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-1，1-二异丙基脲；9) 3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-1,1-diisopropylurea; 10)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-吗啉-4-甲酰胺；10) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-morpholine-4-carboxamide; 11)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-吡咯烷-1-甲酰胺；11) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-pyrrolidine-1-carboxamide; 12)[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸2-苄氧基乙酯；12) [1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-carbamic acid 2-benzyloxyethyl ester; 13)3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-1-甲基-1-丙基脲；13) 3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1-propylurea; 14)[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸叔丁酯；14) [1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-tert-butyl carbamate; 15)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-C-苯基-甲磺酰胺；15) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-C-phenyl-methanesulfonamide; 16)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁烷-1-磺酰胺；16) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butane-1-sulfonamide; 17)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-4-氟苯甲酰胺；17) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-4-fluorobenzamide; 18)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2，2-二甲基丙酰胺；18) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2,2-dimethylpropionamide; 19)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-苯氧基乙酰胺；19) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2-phenoxyacetamide; 20)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；20) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide; 21)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；21) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butanamide; 22)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-环戊烷甲酰胺；22) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-cyclopentanecarboxamide; 23)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-噻吩-2-基乙酰胺；23) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2-thiophen-2-ylacetamide; 24)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-异烟酰胺；24) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-isonicotinamide; 25)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-4-二甲基氨基苯甲酰胺；25) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-4-dimethylaminobenzamide; 26)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；26) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; 27)N-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-6-三氟甲基烟酰胺；27) N-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-6-trifluoromethylnicotinamide; 28)1-叔丁基-3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-脲；28) 1-tert-butyl-3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-urea; 29)1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-乙基脲；29) 1-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-ethylurea; 30)1-苄基-3-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-脲；30) 1-benzyl-3-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-urea; 31)1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-苯乙基脲；31) 1-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-phenylethylurea; 32)1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-噻吩-2-基脲；32) 1-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-thiophen-2-ylurea; 33)1-[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3-噻吩-3-基脲；33) 1-[1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-thiophen-3-ylurea; 34)[1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-氨基甲酸丙酯；34) [1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-propyl carbamate; 35)2，2-二甲基-N-[6-硝基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-丙酰胺；35) 2,2-Dimethyl-N-[6-nitro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-propionamide ; 36)N-[1-(5-氯噻吩-2-基甲基)-6-硝基-2，3-二氢-1H-吲哚-5-基]-2，2-二甲基丙酰胺；36) N-[1-(5-chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indol-5-yl]-2,2-dimethylpropane amides; 37)2-(4-氟苯基)-N-[6-硝基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；37) 2-(4-fluorophenyl)-N-[6-nitro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]- Acetamide; 38)N-[1-(5-氯噻吩-2-基甲基)-6-硝基-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；38) N-[1-(5-chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl )-acetamide; 39)N-[1-(5-氯噻吩-2-基甲基)-6-硝基-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；39) N-[1-(5-chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyl amides; 40)N-[6-氨基-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；40) N-[6-amino-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide ; 41)N-[6-氨基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-2，2-二甲基丙酰胺；41) N-[6-amino-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-2,2-dimethylpropionamide; 42)N-[6-氨基-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-2，2-二甲基丙酰胺；42) N-[6-amino-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2,2-dimethylpropionamide ; 43)N-[6-氨基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；43) N-[6-amino-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-B amides; 44)N-[6-氨基-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；44) N-[6-amino-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide; 45)N-[6-氨基-1-(4-氟苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；45) N-[6-amino-1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide; 46)N-[6-氨基-1-(3-氟-4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；46) N-[6-amino-1-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethyl Butanamide; 47)N-[1-(5-氯噻吩-2-基甲基)-1H-吲哚-5-基]-3，3-二甲基丁酰胺；47) N-[1-(5-chlorothiophen-2-ylmethyl)-1H-indol-5-yl]-3,3-dimethylbutanamide; 48)N-[6-溴-1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；48) N-[6-bromo-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide; 49)N-[6-溴-1-(5-氯噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；49) N-[6-bromo-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide ; 50)N-[1-(4-氯苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；50) N-[1-(4-chlorobenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide; 51)3，3-二甲基-N-[1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；51) 3,3-Dimethyl-N-[1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-butanamide; 52)N-[1-(4-异丙基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；52) N-[1-(4-isopropylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide; 53)N-[1-(3-氟-4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；53) N-[1-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide; 54)N-[1-(6-氯苯并[1，3]二氧杂环戊烯-5-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；54) N-[1-(6-chlorobenzo[1,3]dioxol-5-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3 , 3-dimethylbutanamide; 55)N-[1-(3，5-二甲基-1-苯基-1H-吡唑-4-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；55) N-[1-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-2,3-dihydro-1H-indol-5-yl]- 3,3-Dimethylbutanamide; 56)N-[1-(2-氯-5-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；56) N-[1-(2-chloro-5-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutanamide; 57)N-{1-[5-(4-氯苯氧基)-1，3-二甲基-1H-吡唑-4-基甲基]-2，3-二氢-1H-吲哚-5-基}-3，3-二甲基丁酰胺；57) N-{1-[5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazol-4-ylmethyl]-2,3-dihydro-1H-indole -5-yl}-3,3-dimethylbutanamide; 58)3，3-二甲基-N-[1-(6-对甲苯氧基-吡啶-3-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；58) 3,3-Dimethyl-N-[1-(6-tolyloxy-pyridin-3-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butan amides; 59)N-{1-[6-(4-氯苯基硫基)-吡啶-3-基甲基]-2，3-二氢-1H-吲哚-5-基}-3，3-二甲基丁酰胺；59) N-{1-[6-(4-chlorophenylsulfanyl)-pyridin-3-ylmethyl]-2,3-dihydro-1H-indol-5-yl}-3,3- Dimethylbutanamide; 60)N-{1-[6-(4-氰基苯氧基)-吡啶-3-基甲基]-2，3-二氢-1H-吲哚-5-基}-3，3-二甲基丁酰胺；60) N-{1-[6-(4-cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-1H-indol-5-yl}-3,3- Dimethylbutanamide; 61)3，3-二甲基-N-[1-(6-三氟甲基吡啶-3-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；61) 3,3-Dimethyl-N-[1-(6-trifluoromethylpyridin-3-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butanamide ; 62)3，3-二甲基-N-[1-(3-甲基-苯并[b]噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；62) 3,3-Dimethyl-N-[1-(3-methyl-benzo[b]thiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl ]-Butanamide; 63)N-[1-(6-氟-4H-苯并[1，3]二氧杂环己烯-8-基甲基)-2，3-二氢-1H-吲哚-5-基]-3，3-二甲基丁酰胺；63) N-[1-(6-fluoro-4H-benzo[1,3]dioxin-8-ylmethyl)-2,3-dihydro-1H-indol-5-yl ]-3,3-dimethylbutanamide; 64)3，3-二甲基-N-[1-(6-苯氧基吡啶-3-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；64) 3,3-Dimethyl-N-[1-(6-phenoxypyridin-3-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butanamide; 65)3，3-二甲基-N-[1-(3-甲基-5-苯基-异噁唑-4-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；65) 3,3-Dimethyl-N-[1-(3-methyl-5-phenyl-isoxazol-4-ylmethyl)-2,3-dihydro-1H-indole-5 -yl]-butyramide; 66)N-(1-苯并[b]噻吩-2-基甲基-2，3-二氢-1H-吲哚-5-基)-3，3-二甲基丁酰胺；66) N-(1-benzo[b]thiophen-2-ylmethyl-2,3-dihydro-1H-indol-5-yl)-3,3-dimethylbutanamide; 67)N-{1-[1-(4-氟苯基)-5-甲基-1H-吡唑-4-基甲基]-2，3-二氢-1H-吲哚-5-基}-3，3-二甲基丁酰胺；67) N-{1-[1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-ylmethyl]-2,3-dihydro-1H-indol-5-yl }-3,3-Dimethylbutanamide; 68)3，3-二甲基-N-[1-(5-甲基噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；68) 3,3-Dimethyl-N-[1-(5-methylthiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butanamide; 69)3，3-二甲基-N-[1-(4-吡咯-1-基-苄基)-2，3-二氢-1H-吲哚-5-基]-丁酰胺；69) 3,3-Dimethyl-N-[1-(4-pyrrol-1-yl-benzyl)-2,3-dihydro-1H-indol-5-yl]-butanamide; 70)N-[1-(4-氯苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；70) N-[1-(4-chlorobenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; 71)2-(4-氟苯基)-N-[1-(4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；71) 2-(4-fluorophenyl)-N-[1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-acetamide; 72)2-(4-氟苯基)-N-[1-(4-异丙基苄基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；72) 2-(4-fluorophenyl)-N-[1-(4-isopropylbenzyl)-2,3-dihydro-1H-indol-5-yl]-acetamide; 73)2-(4-氟苯基)-N-[1-(3-氟-4-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；73) 2-(4-fluorophenyl)-N-[1-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-B amides; 74)N-[1-(6-氯苯并[1，3]二氧杂环戊烯-5-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；74) N-[1-(6-chlorobenzo[1,3]dioxol-5-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2 -(4-fluorophenyl)-acetamide; 75)N-[1-(3，5-二甲基-1-苯基-1H-吡唑-4-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；75) N-[1-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-2,3-dihydro-1H-indol-5-yl]- 2-(4-fluorophenyl)-acetamide; 76)N-[1-(2-氯-5-三氟甲基苄基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；76) N-[1-(2-chloro-5-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-B amides; 77)N-{1-[5-(4-氯苯氧基)-1，3-二甲基-1H-吡唑-4-基甲基]-2，3-二氢-1H-吲哚-5-基}-2-(4-氟苯基)-乙酰胺；77) N-{1-[5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazol-4-ylmethyl]-2,3-dihydro-1H-indole -5-yl}-2-(4-fluorophenyl)-acetamide; 78)N-{1-[6-(4-氰基苯氧基)-吡啶-3-基甲基]-2，3-二氢-1H-吲哚-5-基}-2-(4-氟苯基)-乙酰胺；78) N-{1-[6-(4-cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-1H-indol-5-yl}-2-(4 -fluorophenyl)-acetamide; 79)2-(4-氟苯基)-N-[1-(3-甲基-苯并[b]噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；79) 2-(4-fluorophenyl)-N-[1-(3-methyl-benzo[b]thiophen-2-ylmethyl)-2,3-dihydro-1H-indole-5 -yl]-acetamide; 80)N-[1-(6-氟-4H-苯并[1，3]二氧杂环己烯-8-基甲基)-2，3-二氢-1H-吲哚-5-基]-2-(4-氟苯基)-乙酰胺；80) N-[1-(6-fluoro-4H-benzo[1,3]dioxin-8-ylmethyl)-2,3-dihydro-1H-indol-5-yl ]-2-(4-fluorophenyl)-acetamide; 81)2-(4-氟苯基)-N-[1-(6-苯氧基吡啶-3-基甲基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；81) 2-(4-fluorophenyl)-N-[1-(6-phenoxypyridin-3-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-B amides; 82)N-(1-苯并[b]噻吩-2-基甲基-2，3-二氢-1H-吲哚-5-基)-2-(4-氟苯基)-乙酰胺；82) N-(1-benzo[b]thiophen-2-ylmethyl-2,3-dihydro-1H-indol-5-yl)-2-(4-fluorophenyl)-acetamide; 83)2-(4-氟苯基)-N-{1-[1-(4-氟苯基)-5-甲基-1H-吡唑-4-基甲基]-2，3-二氢-1H-吲哚-5-基}-乙酰胺；83) 2-(4-fluorophenyl)-N-{1-[1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-ylmethyl]-2,3-di Hydrogen-1H-indol-5-yl}-acetamide; 84)2-(4-氟苯基)-N-[1-(5-甲基噻吩-2-基甲基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺；和84) 2-(4-fluorophenyl)-N-[1-(5-methylthiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-acetamide ;and 85)2-(4-氟苯基)-N-[1-(4-吡咯-1-基-苄基)-2，3-二氢-1H-吲哚-5-基]-乙酰胺。85) 2-(4-Fluorophenyl)-N-[1-(4-pyrrol-1-yl-benzyl)-2,3-dihydro-1H-indol-5-yl]-acetamide. 23.一种药物组合物，所述药物组合物包含一种或多种药学上可接受的载体或稀释剂以及权利要求1-22中任一项的化合物。23. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or diluents and a compound according to any one of claims 1-22. 24.一种药物组合物用于增加哺乳动物例如人的钾通道中的离子流动的用途，所述药物组合物包含一种或多种药学上可接受的载体或稀释剂以及通式I的化合物或其盐，24. Use of a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or diluents and a compound of general formula I for increasing ion flow in a potassium channel in a mammal such as a human or its salt,
Figure A2004800110190014C1
Figure A2004800110190014C1
 其中in 虚线表示任选的键；Dashed lines indicate optional bonds; R1和R1’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；或R 1 and R 1' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-C 3-8 -cycloalkane (en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo Substitute-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; or R1和R1’与其连接的碳原子一起形成3至8元饱和或不饱和环，所述环任选包含1或2个杂原子；R 1 and R 1' together with the carbon atoms to which they are attached form a 3 to 8 membered saturated or unsaturated ring, said ring optionally comprising 1 or 2 heteroatoms; s为0或1；s is 0 or 1; U为O、NR11、S、SO2、SO2NR11、CO-O或CO-NR11；其中R11选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；或R2和R11与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子；U is O, NR 11 , S, SO 2 , SO 2 NR 11 , CO-O or CO-NR 11 ; wherein R 11 is selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; or R 2 and R 11 together form a 4 to 8 membered A saturated or unsaturated ring optionally comprising 1, 2 or 3 other heteroatoms; R2选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、酰基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤素、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、-NO2、NR10R10’-C1-6-烷(烯/炔)基、NR10R10’-C3-8-环烷(烯)基和NR10R10’-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；R 2 is selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk( En/alkyn)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-C 3-8 -cycloalkane (en)yl-C 1-6 -alk(en/yn)yl, acyl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy -C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halogen, halo-C 1-6 -alk(en/yn)yl, halo-C 3- 8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano, cyano-C 1-6 -alk( En/alkynyl) group, cyano-C 3-8 -cycloalk(en)yl, cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, - NO 2 , NR 10 R 10' -C 1-6 -alk(en/yn)yl, NR 10 R 10' -C 3-8 -cycloalk(en)yl and NR 10 R 10' -C 3-8 -Cycloalk(en)yl-C 1-6 -alk(en/yn)yl; 其中in R10和R10’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3- 8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基，或R 10 and R 10' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-C 3-8 -cycloalkane (en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo Substitute-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, or R10且R10’与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子；R 10 and R 10' together with the nitrogen atom to which they are attached form a 4 to 8 membered saturated or unsaturated ring, said ring optionally comprising 1, 2 or 3 other heteroatoms; 条件是当R2为NO2、卤素或氰基时，s为0；和with the proviso that when R2 is NO2 , halo or cyano, s is 0; and 条件是当R2为氢原子或酰基且s为1时，U为NR11、O或S；The proviso is that when R 2 is a hydrogen atom or an acyl group and s is 1, U is NR 11 , O or S; 其中基团-(U)s-R2连接在吲哚或二氢吲哚的4或6位；Wherein the group -(U) s -R 2 is connected to the 4 or 6 position of indole or indoline; q为0或1；q is 0 or 1; Z为O或S；Z is O or S; X为CO或SO2；条件是当X为SO2时，q为0；X is CO or SO 2 ; the condition is that when X is SO 2 , q is 0; R3选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、杂环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、C1-6-烷(烯/炔)基-杂环烷(烯)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-杂环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、芳基-C1-6-烷(烯/炔)基-杂环烷(烯)基、C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基氧基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基氧基-C3-8-环烷(烯)基、C1-6-烷(烯/炔)基氧基-杂环烷(烯)基、芳基-氧基-C1-6-烷(烯/炔)基、芳基-C1-6-烷(烯/炔)基氧基-C1-6-烷(烯/炔)基、C1-6-烷(烯/炔)基氧基-羰基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基氧基-羰基-C1-6-烷(烯/炔)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基氧基-羰基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-杂环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、羟基-C1-6-烷(烯/炔)基-杂环烷(烯)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-杂环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、卤代-C1-6-烷(烯/炔)基-杂环烷(烯)基、卤代-C1-6-烷(烯/炔)基-芳基、卤代-C3-8-环烷(烯)基-芳基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基-芳基、卤代-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基-芳基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-杂环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、氰基-C1-6-烷(烯/炔)基-杂环烷(烯)基、酰基-C1-6-烷(烯/炔)基、酰基-C3-8-环烷(烯)基、酰基-杂环烷(烯)基、酰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、酰基-C1-6-烷(烯/炔)基-C3-8-环烷(烯)基、酰基-C1-6-烷(烯/炔)基-杂环烷(烯)基和-NR12R12’、任选取代的NR12R12’-C1-6-烷(烯/炔)基、任选取代的NR12R12’-C3-8-环烷(烯)基、任选取代的NR12R12’-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；其中R 3 is selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, heterocycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, C 1-6 -alk(en/yn)yl- Heterocycloalk(en)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-heterocycloalk(en)yl ) group, aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl-C 3- 8 -cycloalk(en)yl, aryl-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, C 1-6 -alk(en/yn)yloxy-C 1 -6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yloxy-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl Oxy-C 3-8 -cycloalk(en)yl, C 1-6 -alk(en/yn)yloxy-heterocycloalk(en)yl, aryl-oxy-C 1-6 -alk (en/yn)yl, aryl-C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl Oxy-carbonyl-C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn) Alkynyl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en) /alkynyl) group, hydroxy-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, hydroxy-C 1-6 -alk(en/yn)yl-heterocycloalkane (en)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-heterocycloalk(en)yl, halo- C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en) ) group, halo-C 1-6 -alk(en/yn)yl-heterocycloalkane(en)yl, halo-C 1-6 -alk(en/yn)yl-aryl, halo-C 3-8 -cycloalk(en)yl-aryl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl-aryl, halo-C 1 -6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl-aryl, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8- Cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, cyano-C 1-6 -alk(en/yn)yl-heterocycloalk(en)yl, acyl- C 1-6 -alk(en/yn)yl, acyl-C 3-8 -cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C 3-8 -cycloalk(en)yl -C 1-6 -alk(en/yn)yl, acyl-C 1-6 -alk(en/yn)yl-C 3-8 -cycloalk(en)yl, acyl-C 1-6 -alk( En/alkyn)yl-heterocycloalkan(en)yl and -NR 12 R 12' , optionally substituted NR 12 R 12' -C 1-6 -alk(en/yn)yl, optionally substituted NR 12 R 12' -C 3-8 -cycloalk(en)yl, optionally substituted NR 12 R 12' -C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl ;in R12和R12’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3- 8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-C3-8-环烷(烯)基、芳基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、羟基-C1-6-烷(烯/炔)基、羟基-C3-8-环烷(烯)基、羟基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基和氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基，或R 12 and R 12' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-C 3-8 -cycloalk(en)yl, aryl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en) ) group, hydroxyl-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, cyano-C 1-6 -alk(en) /alkynyl), cyano-C 3-8 -cycloalk(en)yl and cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, or R12和R12’与其连接的氮原子一起形成4至8元饱和或不饱和环，所述环任选包含1、2或3个其他杂原子；R 12 and R 12' together with the nitrogen atom to which they are attached form a 4 to 8 membered saturated or unsaturated ring, which ring optionally contains 1, 2 or 3 other heteroatoms; 条件是当R3为NR12R12’时，q为0；The condition is that when R 3 is NR 12 R 12' , q is 0; 和and Y表示式II、III、IV、V、VI、XXX和XXXI的基团：Y represents a group of formulas II, III, IV, V, VI, XXX and XXXI: 或 or 其中in 直线表示将Y所示的基团与碳原子连接的键；The straight line represents the bond connecting the group represented by Y to the carbon atom; W为O或S；W is O or S; T为N、NH或O；T is N, NH or O; L为N、C或CH；L is N, C or CH; a为0、1、2或3；a is 0, 1, 2 or 3; b为0、1、2、3或4；b is 0, 1, 2, 3 or 4; c为0或1；c is 0 or 1; d为0、1、2或3；d is 0, 1, 2 or 3; e为0、1或2；e is 0, 1 or 2; f为0、1、2、3、4或5；f is 0, 1, 2, 3, 4 or 5; g为0、1、2、3或4；g is 0, 1, 2, 3 or 4; h为0、1、2或3；h is 0, 1, 2 or 3; j为0、1、2或3；条件是当T为氮原子时，j为0、1、2或3；和当T为NH或氧原子时，j为0、1或2；j is 0, 1, 2 or 3; provided that when T is a nitrogen atom, j is 0, 1, 2 or 3; and when T is NH or an oxygen atom, j is 0, 1 or 2; k为0、1、2、3或4；且k is 0, 1, 2, 3 or 4; and R5各自独立地选自C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基、芳基-C1-6-烷(烯/炔)基、芳基-硫基、芳基-氧基、酰基、C1-6-烷(烯/炔)基氧基、C3-8-环烷(烯)基氧基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基氧基、卤素、卤代-C1-6-烷(烯/炔)基、卤代-C3-8-环烷(烯)基、卤代-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、-CO-NR6R6’、氰基、氰基-C1-6-烷(烯/炔)基、氰基-C3-8-环烷(烯)基、氰基-C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、-NR7R7’、-S-R8和-SO2R8，或两个相邻的R5与其连接的芳基一起形成任选包含一个或两个杂原子的4至8元环；R 5 are each independently selected from C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk (en/yn)yl, aryl, aryl-C 1-6 -alk(en/yn)yl, aryl-thio, aryl-oxy, acyl, C 1-6 -alk(en/yn) )yloxy, C 3-8 -cycloalk(en)yloxy, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy, halogen, halo -C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk (en/yn)yl, -CO-NR 6 R 6' , cyano, cyano-C 1-6 -alk(en/yn)yl, cyano-C 3-8 -cycloalk(en)yl, Cyano-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, -NR 7 R 7' , -SR 8 and -SO 2 R 8 , or two adjacent R together with the aryl to which it is attached forms a 4 to 8 membered ring optionally containing one or two heteroatoms; R6和R6’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基和芳基；R 6 and R 6' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl and aryl; R7和R7’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基和酰基；R 7 and R 7' are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl and acyl; 和and R8选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基、C3-8-环烷(烯)基-C1-6-烷(烯/炔)基、芳基和-NR9R9’；其中R9和R9’独立地选自氢、C1-6-烷(烯/炔)基、C3-8-环烷(烯)基和C3-8-环烷(烯)基-C1-6-烷(烯/炔)基；条件是当R8为-NR9R9’时，R5不为-S-R8。R 8 is selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk( En/alkyn) base, aryl and -NR 9 R 9' ; wherein R 9 and R 9' are independently selected from hydrogen, C 1-6 -alk(en/alkyn) group, C 3-8 -cycloalkane ( alken)yl and C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl; with the proviso that when R 8 is -NR 9 R 9' , R 5 is not -SR 8 . 25.权利要求24的用途，所述用途为预防、治疗或抑制对钾通道中增加的离子流动敏感的疾病，这类疾病优选为中枢神经系统疾病。25. The use according to claim 24 for the prevention, treatment or inhibition of diseases which are sensitive to increased ion flow in potassium channels, such diseases are preferably diseases of the central nervous system. 26.权利要求25的用途，其中所述疾病选自癫痫发作疾病，如惊厥、癫痫和癫痫持续状态。26. The use according to claim 25, wherein the disease is selected from seizure disorders such as convulsions, epilepsy and status epilepticus. 27.权利要求25的用途，其特征在于所述疾病选自神经痛和偏头痛疾病，如异常性疼痛、痛觉过敏性疼痛、幻痛、与糖尿病性神经病相关的神经痛以及与偏头痛相关的神经痛。27. Use according to claim 25, characterized in that the disease is selected from the group consisting of neuralgia and migraine disorders, such as allodynia, hyperalgesia, phantom pain, neuralgia associated with diabetic neuropathy and migraine-associated Neuralgia. 28.权利要求25的用途，其特征在于所述疾病选自焦虑症，如焦虑、广泛性焦虑症、恐慌性焦虑、强迫观念与行为症、社会恐怖、行为焦虑、创伤后应激症、急性应激反应、调节障碍、疑病症、分离焦虑症、广场恐怖症、特异性恐怖症、起因于全身健康状况的焦虑症以及物质诱发的焦虑症。28. Use according to claim 25, characterized in that the disease is selected from anxiety disorders, such as anxiety, generalized anxiety disorder, panic anxiety, obsessive-compulsive disorder, social phobia, behavioral anxiety, post-traumatic stress disorder, acute Stress reactions, adjustment disorders, hypochondria, separation anxiety, agoraphobia, specific phobias, anxiety disorders arising from general health conditions, and substance-induced anxiety disorders. 29.权利要求25的用途，其特征在于所述疾病选自神经变性疾病，如阿尔茨海默氏疾病、亨廷顿舞蹈病、多发性硬化、肌萎缩性侧索硬化症、AIDS-诱发的脑病以及其他由风疹病毒、疱疹病毒、疏螺旋体属以及未知的病原体感染引起的脑病、克罗伊茨费尔特-雅各布病、帕金森氏病、外伤引起的神经变性。29. Use according to claim 25, characterized in that the disease is selected from neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy and Other encephalopathy caused by rubella virus, herpes virus, Borrelia and unknown pathogen infection, Creutzfeldt-Jakob disease, Parkinson's disease, neurodegeneration caused by trauma. 30.权利要求25的用途，其特征在于所述疾病选自神经兴奋过度状态，例如在药物戒毒过程或由于醉酒引起的神经元兴奋过度状态。30. Use according to claim 25, characterized in that the disease is selected from neuronal hyperexcitability states, eg during drug withdrawal or neuronal hyperexcitability due to intoxication.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103508960A (en) * 2012-06-29 2014-01-15 上海先声药物研究有限公司 Benzoheterocyclic derivatives
CN108863893A (en) * 2018-07-09 2018-11-23 湖南博隽生物医药有限公司 Indolinyl derivative and its application in drug
CN112010808A (en) * 2019-05-31 2020-12-01 上海挚盟医药科技有限公司 tetrahydro-1H-benzazepine compounds as potassium channel modulators, and preparation and application thereof

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103508960A (en) * 2012-06-29 2014-01-15 上海先声药物研究有限公司 Benzoheterocyclic derivatives
CN103508960B (en) * 2012-06-29 2017-12-12 江苏先声药业有限公司 Benzheterocyclic derivatives
CN108863893A (en) * 2018-07-09 2018-11-23 湖南博隽生物医药有限公司 Indolinyl derivative and its application in drug
CN112010808A (en) * 2019-05-31 2020-12-01 上海挚盟医药科技有限公司 tetrahydro-1H-benzazepine compounds as potassium channel modulators, and preparation and application thereof
WO2020238917A1 (en) * 2019-05-31 2020-12-03 上海挚盟医药科技有限公司 Tetrahydro-1h-benzazepine compound as potassium channel modulator, preparation method and use thereof
CN112010808B (en) * 2019-05-31 2021-11-30 上海挚盟医药科技有限公司 tetrahydro-1H-benzazepine compounds as potassium channel modulators, and preparation and application thereof
CN113767091A (en) * 2019-05-31 2021-12-07 上海挚盟医药科技有限公司 tetrahydro-1H-benzazepine compounds as potassium channel modulators, and preparation and application thereof

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