WO2023046055A1 - 一种含α-酮骨架的取代杂环类化合物及其用途 - Google Patents

一种含α-酮骨架的取代杂环类化合物及其用途 Download PDF

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WO2023046055A1
WO2023046055A1 PCT/CN2022/120795 CN2022120795W WO2023046055A1 WO 2023046055 A1 WO2023046055 A1 WO 2023046055A1 CN 2022120795 W CN2022120795 W CN 2022120795W WO 2023046055 A1 WO2023046055 A1 WO 2023046055A1
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王进欣
李丽丽
孟涛
尚言国
郝清静
贾一鹤
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中国药科大学
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Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a substituted heterocyclic compound containing an ⁇ -ketone skeleton, in particular to a substituted heterocyclic FAAH inhibitor containing an ⁇ -ketone skeleton, and its preparation for prevention and/or treatment and Drug application in FAAH-associated diseases.
  • Chronic pain is not an early warning to prevent physical injury or disease, but the result of a malfunction in neural mechanisms, which usually lasts or recurs for more than 3 to 6 months. Accumulating evidence suggests that chronic pain is a multifactorial condition that exacerbates underlying mood disorders such as anxiety and depression, which in turn complicates drug treatment. The high prevalence and long duration of chronic pain not only significantly reduce the health status and quality of life of individuals, but also bring a huge economic burden to the whole society.
  • the drugs used to treat chronic pain mainly include non-opioid analgesics such as paracetamol and non-steroidal anti-inflammatory drugs; opioids such as codeine, dihydrocodeine, fentanyl and buprenorphine; Antidepressants such as tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitors, and antiepileptic drugs such as gabapentin and pregabalin exhibit special analgesic effects when opioid therapy is ineffective.
  • non-opioid analgesics such as paracetamol and non-steroidal anti-inflammatory drugs
  • opioids such as codeine, dihydrocodeine, fentanyl and buprenorphine
  • Antidepressants such as tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitors
  • antiepileptic drugs such as gabapentin and pregabalin exhibit special analgesic effects when opioid therapy is ineffective.
  • the endocannabinoid system is widely distributed in the central and peripheral nervous systems, and plays a key role in regulating the occurrence and development of pain, anxiety, depression, cardiovascular and other diseases. It is mainly composed of endogenous cannabinoid N-arachidonic acid ethanolamine (AEA), N-arachidonic acid glycerol (2-AG), cannabinoid receptors (CB1, CB2), and endogenous cannabinoid synthesis, Enzymes involved in degradation.
  • AEA is the most widely studied endocannabinoid receptor (CB1, CB2) agonist, which can be decomposed into ethanolamine and AA by fatty amide hydrolase (FAAH) in vivo and inactivated.
  • ECS endocannabinoid system
  • FAAH Fatty amide hydrolase
  • AEA lipid molecule fatty amide
  • FAAH enzyme is the main enzyme that regulates the metabolism of endogenous lipid molecule fatty amide. Inhibition of FAAH increases endogenous fatty acid amide levels.
  • FAAH inhibitors can exert antidepressant effects through anti-inflammation, neuroprotection and improving HPA axis disorders; meanwhile, FAAH inhibitors can also activate G proteins, inhibit adenylyl cyclase and regulate Na + / K + ion channels play an analgesic role. It was also found that the endocannabinoid system plays an analgesic role in chronic pain mainly by inhibiting glial cell activation and central sensitization.
  • the present invention provides a substituted heterocyclic compound containing ⁇ -ketone skeleton with FAAH inhibitory activity and its application.
  • a substituted heterocyclic compound containing an ⁇ -keto skeleton is provided, which is a compound represented by formula I or a pharmaceutically acceptable salt thereof:
  • Ar is unsubstituted, monosubstituted or polysubstituted aromatic heterocycle
  • R 1 represents H or an aromatic ring or an aromatic heterocyclic ring
  • R4 is selected from H, C1-C8 straight chain halogenated alkanes or halogenated branched chain alkanes, halogenated cycloalkanes, C1-C8 straight chain alkanes Or branched alkanes, cycloalkanes;
  • A is a 4-7 membered saturated or unsaturated heterocycle containing 1-2 heteroatoms N, S or O;
  • R 2 and R 3 each independently represent H or a substituent.
  • Ar is an unsubstituted, monosubstituted or polysubstituted aromatic heterocycle, wherein the aromatic heterocycle is selected from: furan, thiophene, pyrrole, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, triazole , 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, pyridine, pyrimidine, pyridazine, benzo Oxazole, benzothiazole, purine, quinoline, isoquinoline, indole, indazole, oxazolo[4,5-b]pyridine, oxazolo[5,4-b]pyridine.
  • the aromatic heterocycle is selected from: furan, thiophene, pyrrole, oxazole, isoxazole, imidazole, pyrazole,
  • the aromatic heterocycle is selected from the following groups:
  • R represents H, an aromatic ring or an aromatic heterocyclic ring, wherein the aromatic ring or aromatic heterocyclic ring is unsubstituted, monosubstituted or multi-substituted, and the aromatic ring or aromatic heterocyclic ring is selected from phenyl, furyl, thienyl, pyrrole oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole Base, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxygen indenyl, indolyl, quinolinyl, isoquinolyl , Indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolopyridyl
  • the aromatic ring is selected from The substituents on the aromatic ring are selected from H, F, Cl, Br, I, methoxy, methyl.
  • L is selected from -CO- or -CH 2 -;
  • A is a 5-6 membered saturated or unsaturated heterocycle containing 1-2 heteroatoms N or O;
  • R is selected from H, methyl, ethyl, acetyl, phenyl, pyridyl, methoxyl, propionyl, methoxyacetyl, ethoxyacetyl; preferably H, methyl;
  • R 3 is selected from H, F, Cl, Br, I, CF 3 , CN, hydroxyl, methoxy, methyl, nitro, mercapto, carboxyl, vinyl, bromomethyl, cyanomethyl, Aryl, heterocyclyl, C1-C10 straight-chain or branched-chain alkanes, cycloalkane, C1-C10 straight-chain or branched-chain alkaneoxy, C1-C10 straight-chain or branched-chain alkanes substituted mercapto, C1-C10 straight-chain Or branched alkane ester group; preferably H, F, Cl, Br, I.
  • the second aspect of the present invention provides the preparation method of the compound shown in formula I,
  • R 1 is H
  • Ar is a single heterocycle containing two heteroatoms such as oxazole, thiazole, or a condensed heterocycle such as benzoxazole or benzothiazole
  • composition which contains a therapeutically effective amount of one or more of the compounds or their pharmaceutically acceptable salts or stereoisomers or prodrugs thereof and a pharmaceutically acceptable carrier;
  • the pharmaceutically acceptable carrier is a filler, a lubricant, an emulsifier, a wetting agent, a coloring agent, a flavoring agent, a stabilizer, an antioxidant, and a preservative.
  • the compound and the pharmaceutical composition are used as FAAH inhibitors in the preparation of drugs for preventing and/or treating diseases related to FAAH.
  • the diseases related to FAAH include inflammatory diseases, rheumatoid arthritis, hepatitis, liver fibrosis, autoimmune diseases, pain, depression, comorbidity of pain and depression, autism, social phobia, Tourette Syndrome, neurodegenerative diseases, anxiety posttraumatic stress (PTSD), cannabinoid use disorders, drug withdrawal, antineoplastic therapy.
  • the present invention proves that the substituted heterocyclic compound containing ⁇ -ketone skeleton has good inhibitory activity on FAAH, and is suitable for diseases related to FAAH.
  • Figure 1 is the anti-inflammatory activity test of compounds (*p ⁇ 0.01 vs control group, #p ⁇ 0.05 vs LPS group, ##p ⁇ 0.01 vs LPS group);
  • Figure 2 is the experimental study on sugar water preference (*p ⁇ 0.01 vs control group, #p ⁇ 0.01 vs Model group);
  • Figure 3 is an open field experiment study (*, P value compared to control group (*P ⁇ 0.01); # , P value compared to model group ( # P ⁇ 0.05, ## P ⁇ 0.01).).
  • Embodiment 1 the preparation of compound
  • N-Boc-piperidone (1g, 5mmol, 1eq) and p-toluenesulfonyl hydrazide (935mg, 5mmol, 1eq) were dissolved in methanol and reacted at room temperature for 6h. After the reaction was completed, it was concentrated under reduced pressure to obtain 1.56 g of a white solid with a yield of 84%.
  • Benzaldehyde (1 g, 9.42 mmol, 1 eq) was dissolved in methanol, p-toluenesulfonylisonitrile (2.023 g, 10.362 mmol, 1.1 eq) and K2CO3 (2.598 g , 18.8 mmol, 2 eq) were added, Reflux reaction at 80°C for 1.5h. After the reaction, the methanol was concentrated under reduced pressure to remove methanol, and the insoluble matter K 2 CO 3 was dissolved and filtered out with DCM. The filtrate was concentrated under reduced pressure and then purified by column chromatography to obtain 1.03 g of a solid with a yield of 74%.
  • 2-Phenyl-1,3,4-oxadiazole (323mg, 2.21mmol, 1.2eq) was dissolved in anhydrous THF, and n-BuLi (0.88ml, 2.21mmol, 1.2eq) was slowly added at -40°C After stirring for 30 min, a THF solution of 1-Boc-4-[(methoxy)methylcarbamoyl]piperidine (500mg, 1.84mmol, 1eq) was added, and then warmed to room temperature for overnight reaction.
  • 3-Pyridinecarbohydrazide (1g, 7.3mmol, 1eq) was dissolved in trimethyl orthoformate, p-toluenesulfonic acid (126mg, 0.73mmol, 0.1eq) was added, and the mixture was refluxed at 120°C for 1.5h. After the reaction was completed, it was diluted with EA, washed three times with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 915 mg of a white solid with a yield of 85%.
  • 2-Thienyl hydrazide (1.4g, 9.85mmol, 1eq) was dissolved in trimethyl orthoformate, p-toluenesulfonic acid (170mg, 0.99mmol, 0.1eq) was added, and the mixture was refluxed at 120°C for 1.5h. After the reaction, it was diluted with EA, washed three times with water and saturated brine, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain 1.2 g of a colorless oily liquid with a yield of 80.08%.
  • 2-(thiophen-2-yl)-1,3,4-oxadiazole (1.2g, 7.89mmol, 1eq) was dissolved in anhydrous THF, and LDA (6ml, 11.84mmol, 1.5 eq), after stirring for 30min, a THF solution of 1-Boc-4-piperidinecarbaldehyde (1.7g, 7.89mmol, 1eq) was added, then raised to room temperature, and the reaction was continued for 3h.
  • 2-(3-methoxypyridin-2-yl)-1,3,4-oxadiazole (251 mg, 1.42 mmol, 1 eq) was dissolved in anhydrous THF, and LDA (1.4 ml, 2.84mmol, 2eq), after stirring for 30min, a THF solution of 1-Boc-4-piperidinecarbaldehyde (302mg, 1.42mmol, 1eq) was added, then warmed to room temperature, and the reaction was continued for 3h.
  • Embodiment 2 In vitro FAAH enzyme inhibitory activity test
  • FAAH can hydrolyze AEA in cells to generate ethanolamine.
  • different enzyme activities catalyze and generate different amounts of products.
  • the level of enzyme activity can be inspected.
  • the present invention carries out experimental design according to this principle. According to the instructions of the FAAH kit, dilute a certain concentration of FAAH, add buffer, fluorescently labeled reaction substrates, and then add compounds of various concentrations, set up a blank control group, JZL-195 positive control group, and use a microplate reader to perform the reaction after the reaction is completed. Fluorescent analysis, and finally calculate the inhibition rate.
  • the compounds of the present invention have good FAAH inhibitory activity.
  • BV2 cells treated with LPS were used to construct a neuroinflammation model, and whether compound I-11 could inhibit neuroinflammation was investigated by detecting the release level of inflammatory factors (TNF- ⁇ , IL-1 ⁇ ).
  • the results are shown in Figure 1 and Table 1, the expression levels of inflammatory factors (TNF- ⁇ , IL-1 ⁇ ) were extremely low in the cells of the Control group; after treatment with LPS, the expression levels of TNF- ⁇ and IL-1 ⁇ were significantly increased. High (p ⁇ 0.01); after treatment with LPS, the expression levels of TNF- ⁇ and IL-1 ⁇ were significantly increased (p ⁇ 0.01);
  • Inhibitor 1 can reduce the expression of inflammatory factors TNF- ⁇ and IL-1 ⁇ in a dose-dependent manner to cells pretreated with compound I-11. At high concentrations (20 ⁇ M), it can restore inflammatory factors close to normal levels. The experimental results show that compound 1 can effectively inhibit the inflammatory response of BV2 cells induced by LPS, has a good anti-neuroinflammatory response, and has the potential for further development.
  • the analgesic activity of compound I-11 was tested using the acetic acid writhing test of mice as a pain model, and the information of the experimental animals and the experimental procedures are as follows.
  • mice Healthy ICR mice, clean grade, weighing 20-25g.
  • the animal room meets the requirements of a clean laboratory, with a temperature of 20-22°C, a humidity of 40%-70%, and control of 12 hours of light/12 hours of darkness (8:00-20:00 light time).
  • the mice were kept in plastic cages (volume 280 ⁇ 150 ⁇ 180mm), 10 mice per cage, male and female were reared separately, free to eat and drink. use.
  • the adaptive feeding time of animals was 7 days. All handling of the accompanying animals followed the requirements of the Ethics Committee of the International Association for the Study of Pain. The mice were kept in the animal room after purchase.
  • Glacial acetic acid and normal saline were purchased from the Reagent Library of China Pharmaceutical University, and I-11 was a compound synthesized in the laboratory (purity>98%)
  • mice with saturated picric acid solution, number 1 for the left forelimb, number 2 for the left hindlimb, number 3 for the right forelimb, number 4 for the right hindlimb, and number 5 for the head.
  • the head plus the left forelimb is No. 6
  • the head plus the left hind limb is No. 7
  • the head plus the right forelimb is No. 8
  • the head plus the right hind limb is No. 9
  • the tail is No. 10.
  • mice writhing test was used to study the analgesic activity of the samples.
  • Kunming mice weighing 20 ⁇ 2 g were divided into 4 groups randomly, with 10 mice in each group. These included high, medium, and low dose groups of samples and a control group.
  • mice were subcutaneously administered to mice at high (5mg ⁇ kg -1 ), medium (2.5mg ⁇ kg -1 ) and low (1.25mg ⁇ kg -1 ) doses, and the control group was given the same amount of normal saline (0.9% NaCl)
  • each mouse was intraperitoneally injected with 0.7% glacial acetic acid 10mL/kg, observed and recorded the number of times of writhing and the latency of mice in 15 minutes after injecting glacial acetic acid, calculated the analgesic percentage, and carried out statistical processing, The significance was judged by T test.
  • Analgesic percentage (%) (average writhing times of the control group - average writhing times of the administration group)/average writhing times of the control group
  • mice According to the acetic acid writhing test of mice, the blank control group, the morphine group, and the I - 11 group were compared for the number of mice writhing within 15 minutes.
  • the inhibition rate of the compound I-11 was 87.1%, which indicated that the compound I-11 had obvious analgesic activity.
  • Body weight (180g-200g) male SD rats were randomly divided into 6 groups, 8 in each group, grouped as follows:
  • the normal group was fed normally, and the rats in each group were intraperitoneally injected with reserpine (0.2 mg/kg) once a day for three days. After successful modeling with reserpine, the corresponding drugs were given according to the groups. After continuous administration for two weeks, the sugar water consumption test, the open field test and the forced swimming test were carried out in sequence.
  • the American Psychiatric Association believes that the important feature of depression is the decline of reward responsiveness, that is, anhedonia, and the sugar water preference experiment is a better evaluation index for detecting the reward responsiveness of experimental animals.

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Abstract

本发明公开了一种含α-酮骨架的取代杂环类化合物及其用途，涉及药物化学领域，具体公开一种含α-酮骨架的取代杂环类化合物或其药学上可接受的盐，含有这些化合物的药用组合物以及它们的医药用途，特别是作为脂肪酰胺水解酶（FAAH）抑制剂，在制备预防或治疗与FAAH相关疾病的药物中的应用，包括炎症性疾病、类风湿性关节炎、肝炎、肝纤维化、自身免疫病、疼痛、抑郁、疼痛抑郁共病、自闭症、社交恐惧症、图雷特氏综合症、神经退行性疾病、焦虑创伤后应激（PTSD）、大麻素使用紊乱疾病、药物戒断、抗肿瘤治疗。

Description

一种含α-酮骨架的取代杂环类化合物及其用途 技术领域
本发明属于药物化学领域，涉及一种含α-酮骨架的取代杂环类化合物，具体涉及一种含α-酮骨架的取代杂环类FAAH抑制剂，及其在制备预防和/或治疗与FAAH相关疾病的药物中的应用。
背景技术
慢性疼痛不是预防身体伤害或疾病的早期预警，而是神经机制失常的结果，通常持续或复发超过3～6个月。越来越多的证据表明，慢性疼痛是一种多因素疾病，会加剧潜在的焦虑和抑郁等情绪障碍，进而使药物治疗更复杂。慢性疼痛患病率高、持续时间长，不仅显著降低个人的健康状况和生活质量，还会对整个社会带来巨大的经济负担。
目前，用于治疗慢性疼痛的药物主要包括非阿片类镇痛药物如扑热息痛和非甾体抗炎药；阿片类药物如可待因、双氢可待因、芬太尼和丁丙诺啡；在阿片类药物治疗无效下，抗抑郁药物如三环类抗抑郁药和5-羟色胺和去甲肾上腺素再摄取抑制剂，抗癫痫药物如加巴喷丁和普瑞巴林表现出特殊的镇痛效应。但是非甾体抗炎药的长期使用会带来严重的胃肠道、肾脏副作用，还可能增加心血管风险；阿片类药物的使用会引起呼吸抑制、成瘾、恶心、意识混乱和免疫抑制等副作用，不适于慢性疼痛的长期药物治疗。因此，开发新型的镇痛药物具有重要的研究价值和科学意义。
内源性大麻素系统广泛分布于中枢和外周神经系统，在调节疼痛、焦虑、抑郁、心血管等多种疾病的发生发展中发挥着关键作用。其主要由内源性大麻素N-花生四烯酸乙醇胺(AEA)、N-花生四稀酸甘油(2-AG)，大麻素受体(CB1,CB2)，与内源性大麻素合成、降解有关的酶类组成。AEA是研究最为广泛的内源性大麻素受体(CB1,CB2)激动剂，其在体内可被脂肪酰胺水解酶(FAAH)分解为乙醇胺和AA而失活。
研究表明：内源性大麻素系统(ECS)的保护作用均是通过CB受体的激活实现的。诸多临床前研究证实基因敲除或者药物抑制剂使FAAH失活，均能使机体内源性的AEA含量升高，继而激活CB、TRPV1等受体，发挥抗炎、镇痛、抗抑郁、调节大麻素紊乱、药物戒断等多种生理作用。ECS在许多病理生理状态下上调，如炎症、神经退行性疾病、胃肠道反应、代谢和心血管疾病、疼痛和癌症，在抑制疾病进展或减少体征和症状方面发挥自我保护作用。因此，抑制内源性大麻素降解是治疗多种疾病的一种治疗手段。
在生物体内，内源性大麻素被释放到细胞外，通过细胞吸收或水解被迅速清除。脂肪酰胺水解酶(FAAH)是AEA主要的代谢水解酶，FAAH酶是调控内源性脂质分子脂肪酰胺代 谢的主要酶。抑制FAAH可以提高内源性脂肪酰胺水平。研究表明，FAAH抑制剂可通过抗炎、神经保护以及改善HPA轴紊乱等多种途径发挥抗抑郁作用；同时FAAH抑制剂也能够通过激活G蛋白，抑制腺苷酸环化酶和调节Na +/K +离子通道发挥镇痛作用。同时发现内源性大麻素系统主要通过抑制胶质细胞活化和中枢敏化在慢性疼痛中发挥镇痛作用。
通过抑制FAAH活性，可以减少AEA的代谢，进而激活CB受体，发挥镇痛作用。近年来，通过抑制FAAH间接激活CB受体已成为镇痛药物的研究热点，有些FAAH抑制剂已经进入临床研究，为开发新型的安全有效的镇痛药物和其他相关疾病治疗药物提供了新的途径。
发明内容
目的：本发明提供一种具有FAAH抑制活性的含α-酮骨架的取代杂环类化合物及其用途。
技术方案：为解决上述技术问题，本发明采用的技术方案为：
在本发明的第一方面，提供了一种含α-酮骨架的取代杂环类化合物，为式I所示的化合物或其药学上可接受的盐：
Figure PCTCN2022120795-appb-000001
其中，
Ar为无取代、单取代或多取代芳杂环；
R 1表示H或芳环或芳杂环；
L表示连接链，选自-O-、-S-、-NR 4-、
Figure PCTCN2022120795-appb-000002
或-(CH 2) n-,n＝0,1,2,3；R4选自H，C1-C8直链卤代烷烃或卤代支链烷烃基、卤代环烷烃，C1-C8直链烷烃或支链烷烃、环烷烃；
A为4-7元饱和或不饱和的含有1-2个杂原子N、S或O的杂环；
R 2、R 3分别独立的表示H或取代基。
(1)Ar为无取代、单取代或多取代芳杂环，其中芳杂环选自：呋喃、噻吩、吡咯、噁唑、异噁唑、咪唑、吡唑、噻唑、异噻唑、三氮唑、1,3,4-噁二唑、1,3,4-噻二唑、1,2,4-噁二唑、1,2,4-噻二唑、吡啶、嘧啶、哒嗪、苯并噁唑、苯并噻唑、嘌呤、喹啉、异喹啉、吲哚、吲唑、噁唑并[4,5-b]吡啶、噁唑并[5,4-b]吡啶。
在一些实施例中，芳杂环选自下述基团：
Figure PCTCN2022120795-appb-000003
(2)R 1表示H、芳环或芳杂环，其中芳环或芳杂环为无取代、单取代或多取代，芳环或芳杂环选自苯基、呋喃基、噻吩基、吡咯基、噁唑基、异噁唑基、咪唑基、吡唑基、噻唑基、异噻唑基、三氮唑基、1,3,4-噁二唑基、1,3,4-噻二唑基、1,2,4-噁二唑基、1,2,4-噻二唑基、吡啶基、嘧啶基、哒嗪基，氧茚基、吲哚基、喹啉基、异喹啉基、吲唑基、苯并噁唑基、苯并噻唑基、嘌呤基、噁唑并吡啶基；芳环或芳杂环上的取代基选自H、F、Cl、Br、I、CF 3、CN、羟基、甲氧基、甲基、硝基、巯基、羧基、乙烯基、溴甲基、氰甲基、C1-C10直链或支链烷烃氧基、C1-C10直链卤代烷烃或卤代支链烷烃基、卤代环烷烃，C1-C10直链烷烃或支链烷烃、环烷烃，C1-C10直链或支链烷烃取代巯基、C1-C10直链或支链烷烃酰胺基、C1-C10直链或支链烷烃酯基。
在一些实施例中，R 1中，芳环选自
Figure PCTCN2022120795-appb-000004
芳环上的取代基选自H、F、Cl、Br、I、甲氧基、甲基。
在一些实施例中，L选自-CO-或-CH 2-；
和/或，A为5-6元饱和或不饱和的含有1-2个杂原子N或O的杂环；
和/或，R 2选自H、甲基、乙基、乙酰基、苯基、吡啶基、甲氧酰基、丙酰基、甲氧乙酰基、乙氧乙酰基；优选为H、甲基；
和/或，R 3选自H、F、Cl、Br、I、CF 3、CN、羟基、甲氧基、甲基、硝基、巯基、羧基、乙烯基、溴甲基、氰甲基、芳基、杂环基，C1-C10直链烷烃或支链烷烃、环烷烃，C1-C10直链或支链烷烃氧基，C1-C10直链或支链烷烃取代巯基、C1-C10直链或支链烷烃酯基；优选为H、F、Cl、Br、I。
在一些实施例中，
Figure PCTCN2022120795-appb-000005
选自下述基团：
Figure PCTCN2022120795-appb-000006
进一步的，式I所示的化合物选自：
Figure PCTCN2022120795-appb-000007
Figure PCTCN2022120795-appb-000008
Figure PCTCN2022120795-appb-000009
本发明的第二个方面，提供了式I所示的化合物的制备方法，
Figure PCTCN2022120795-appb-000010
当R 1为H，Ar为呋喃基、噻吩基、吡啶基，或稠杂环如氧茚基等时，采用第一种制备方法构建Intermediate 1：
Figure PCTCN2022120795-appb-000011
当R 1为H，Ar为含两个杂原子的单杂环如噁唑、噻唑，或稠杂环如苯并噁唑、苯并噻唑时，采用第二种制备方法构建Intermediate 1：
Figure PCTCN2022120795-appb-000012
当R1为无取代、单取代或多取代芳环，Ar为呋喃基、1,3,4-噁二唑基等时，采用第三种制备方法构建Intermediate 1：
Figure PCTCN2022120795-appb-000013
另一方面，一种药物组合物，其中含有治疗有效量的一种或多种所述的化合物或其药学上可接受的盐或立体异构体或其前药和药学上可接受的载体；
所述药学上可接受的载体为填充剂、润滑剂、乳化剂、润湿剂、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂。
本发明的第三个方面，所述的化合物、所述的药物组合物作为FAAH抑制剂，在制备预防和/或治疗与FAAH相关疾病的药物中的应用。
进一步的，所述与FAAH相关疾病包括炎症性疾病、类风湿性关节炎、肝炎、肝纤维化、自身免疫病、疼痛、抑郁、疼痛抑郁共病、自闭症、社交恐惧症、图雷特氏综合症、神经退行性疾病、焦虑创伤后应激(PTSD)、大麻素使用紊乱疾病、药物戒断、抗肿瘤治疗。
本发明通过大量的现代药理科学研究，证实了含α-酮骨架的取代杂环类化合物对FAAH具有较好的抑制活性，并适用于与FAAH相关的疾病。
附图说明
图1为化合物抗炎活性测试(*p<0.01 vs control group,#p<0.05 vs LPS group,##p<0.01 vs LPS group)；
图2为糖水偏好实验研究(*p<0.01 vs control group,#p<0.01 vs Model group)；
图3为旷场实验研究(*,P value compared to control group(*P<0.01)； #,P value compared to model group( #P<0.05, ##P<0.01).)。
具体实施方式
为了进一步阐明本发明，下面给出一系列实施例，这些实施例完全是例证性的，它们仅用来对本发明具体描述，不应当理解为对本发明的限制。
实施例1：化合物的制备
5-氯-1-甲基-1H-吲哚-2-羧酸乙酯
将5-氯-2-吲哚甲酸乙酯(1g，4.47mmol，1eq)溶于N,N-二甲基甲酰胺中，加入氢化钠(215mg，8.94mmol，2eq)，氮气保护下，80℃搅拌1小时后，加入碘甲烷(834μl，13.41mmol，3eq)，TLC监测反应进程。反应结束后，加入饱和氯化铵淬灭，二氯甲烷(3×30mL)萃取，有机相用无水硫酸钠干燥，减压蒸除溶剂，经柱层析分离纯化得淡黄色固体817mg，收率77％。 1H NMR(400MHz,DMSO-d 6)δ7.76(d,J＝2.1Hz,1H),7.64(d,J＝9.0Hz,1H),7.35(dd,J＝8.9,2.1Hz,1H),7.24(s,1H),4.33(q,J＝7.1Hz,2H),4.02(s,3H),1.34(t,J＝7.1Hz,3H)ppm.
5-氯-1-甲基-1H-吲哚-2-羧酸
将5-氯-1-甲基-1H-吲哚-2-羧酸乙酯(817mg，3.45mmol，1eq)溶于甲醇水溶液，加入氢氧化钠(552mg，13.8mmol，4eq)，60℃搅拌2小时后，加入1mol/L盐酸调节pH至2，有大量固体析出，抽滤，滤饼干燥得白色固体646mg，收率90％。 1H NMR(400MHz,DMSO-d 6)δ13.10(s,1H),7.74(d,J＝2.1Hz,1H),7.61(dt,J＝9.0,0.8Hz,1H),7.34-7.31(m,1H),7.19(d,J＝0.9Hz,1H)ppm.
1-甲基-1H-吲哚-2-羧酸乙酯
采用与6-氯-1-甲基-1H-吲哚-2-羧酸乙酯相同的合成方法，以吲哚-2-羧酸乙酯为原料，得淡黄色固体235mg，收率44％。 1H NMR(400MHz,CDCl 3)δ7.81-7.79(m,1H),7.48-7.45(m,2H),7.38-7.35(m,1H),7.30-7.29(m,1H),4.29(q,J＝6.4Hz,2H),1.36(t,J＝6.4Hz,3H)ppm.
1-甲基-1H-吲哚-2-羧酸
将1-甲基-1H-吲哚-2-羧酸乙酯280mg，1.38mmol，1eq)溶于甲醇水溶液，加入氢氧化钠(221mg，5.52mmol，4e q)，60℃搅拌下反应2小时，TLC监测反应进程。反应结束后，加入1mol/L盐酸调节pH至2，仅少量固体析出，所以用二氯甲烷：甲醇＝10:1萃取三次， 合并的有机相加入无水硫酸钠干燥30分钟，抽滤，滤液减压蒸除溶剂得灰白色固体203mg，收率84％。 1H NMR(400MHz,DMSO-d 6)δ12.96(s,1H),7.64(dd,J＝8.1,1.1Hz,1H),7.44(dd,J＝8.3,1.1Hz,1H),7.24(ddd,J＝8.2,6.9,1.2Hz,1H),7.09-7.04(m,2H),3.37(s,3H)ppm.
4-(2-甲苯磺酰基亚苄基)哌啶-1-甲酸叔丁酯
将N-Boc-哌啶酮(1g，5mmol，1eq)和对甲基苯磺酰肼(935mg，5mmol，1eq)溶于甲醇中，室温反应6h。反应结束后减压浓缩即可得到白色固体1.56g，收率84％。 1H NMR(300MHz,DMSO-d6)δ10.29(s,1H),7.79–7.71(m,2H),7.42(d,J＝8.0Hz,2H),3.41(q,J＝6.3Hz,4H),2.41(s,3H),2.37(d,J＝6.1Hz,2H),2.24(t,J＝6.1Hz,2H),1.42(s,9H).
4-烟碱基哌啶-1-羧酸叔丁酯
将4-(2-甲苯磺酰基亚苄基)哌啶-1-甲酸叔丁酯(500mg，1.36mmol，1eq)和3-吡啶甲醛(127μl，1.36mmol，1eq)溶于无水1,4-二氧六环中，加入碳酸铯(220mg，2.04mmol，1.5eq)，升至110℃搅拌3小时后，加饱和氯化铵溶液淬灭，再用二氯甲烷(3×35mL)萃取，合并的有机相加入无水硫酸钠干燥，减压蒸除溶剂，经柱层析分离纯化得淡黄色油状物190mg，收率48％。 1H NMR(300MHz,DMSO-d 6)δ9.19(dd,J＝2.3,0.9Hz,1H),8.83(dd,J＝4.8,1.7Hz,1H),8.35(dt,J＝8.0,2.0Hz,1H),7.61(ddd,J＝7.9,4.8,0.9Hz,1H),4.00(d,J＝13.0,2H),3.69(tt,J＝11.3,3.6Hz,1H),2.95(s,2H),1.82(dd,J＝13.6,3.5Hz,2H),1.50-1.44(m,2H),1.43(s,9H)ppm.
4-异烟酰胺基哌啶-1-羧酸叔丁酯
将4-(2-甲苯磺酰基亚苄基)哌啶-1-甲酸叔丁酯(500mg，1.36mmol，1eq)和3-吡啶甲醛(127μl，1.36mmol，1eq)溶于无水1,4-二氧六环中，加入碳酸铯(220mg，2.04mmol，1.5eq)，升至110℃搅拌3小时后，加饱和氯化铵溶液淬灭，再用二氯甲烷(3×35mL)萃取，合并的有机相加入无水硫酸钠干燥，减压蒸除溶剂，经柱层析分离纯化得淡黄色油状物388mg，收率98％。 1H NMR(400MHz,DMSO-d 6)δ8.83-8.81(m,2H),7.86-7.84(m,2H),3.96(d,J＝13.2Hz,2H),3.63(tt,J＝11.3,3.6Hz,1H),2.92(s,2H),1.79(d,J＝13.2Hz,2H),1.42-1.39(m,11H)ppm.
哌啶-4-基(吡啶-4-基)甲酮
将4-异烟酰胺基哌啶-1-羧酸叔丁酯溶于HCl/EA中，室温搅拌半小时，抽滤，干燥得淡黄色固体230mg，收率82％。 1H NMR(400MHz,DMSO-d 6)δ7.82-7.73(m,2H),7.44-7.36(m,2H),3.17-3.14(m,4H),2.76-2.67(m,1H),2.63-2.59(m,1H),2.40-2.37(m,4H)ppm.
(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮(I-1)
Figure PCTCN2022120795-appb-000014
将哌啶-4-基(吡啶-4-基)甲酮(200mg，0.885mmol，1.0eq)和5-氯-1-甲基-1H-吲哚-2- 羧酸(185mg，0.885mmol，1.0e q)溶于N,N-二甲基甲酰胺中，加入EDCI(85mg，0.442mmol，0.5e q)、1-羟基苯并三唑(60mg，0.442mmol，0.5eq)和N-甲基吗啉(195μl，1.77mmol，1.0e q)，室温搅拌0.5小时后，加入30mL水，用乙酸乙酯(3×30mL)萃取，合并的有机相加入无水硫酸钠干燥，减压蒸除溶剂，经柱层析分离纯化得白色固体112mg，收率33％。 1H NMR(400MHz,DMSO-d 6)δ8.84-8.83(m,2H),7.88-7.87(m,2H),7.65(d,J＝2.1Hz,1H),7.56(d,J＝8.8Hz,1H),7.24(dd,J＝8.8,2.1Hz,1H),6.65(s,1H),4.51(s,1H),4.09-3.93(m,1H),3.84-3.78(m,1H),3.76(s,3H),3.18-2.17(m,2H),2.02-1.90(m,2H),1.61-1.51(m,2H)ppm；HRMS(ESI +):m/z[M+H] +calcd for C 21H 21ClN 3O 2,382.1317；found 382.1370.
(4-异烟酰胺基哌啶-1-基)(1-甲基-1H-吲哚-2-基)甲酮(I-2)
Figure PCTCN2022120795-appb-000015
采用与(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮相同的合成方法，以哌啶-4-基(吡啶-4-基)甲酮和1-甲基-1H-吲哚-2-羧酸为原料，得米色固体208mg，收率68％。 1H NMR(400MHz,DMSO-d 6)δ8.84-8.82(m,2H),7.89-7.87(m,2H),7.61-7.59(m,1H),7.51(d,J＝8.3Hz,1H),7.25(tt,J＝8.0,1.1Hz,1H),7.12-7.07(m,1H),6.66(s,1H),4.46-4.10(m,2H),3.83-3.78(m,1H),3.76(s,3H),3.23-3.18(m,2H),1.90(s,2H),1.61-1.51(m,2H)ppm； 13C NMR(101MHz,CDCl 3)δ200.95,162.73,151.19,141.63,136.28,132.86,127.28,125.97,123.75,121.19,120.75,110.95,102.70,43.62,31.32,28.37ppm；HRMS(ESI +):m/z[M+H] +calcd for C 21H 21N 3O 2,348.1707；found 348.1757.
4-吡啶甲酸叔丁酯-1-羧酸叔丁酯
采用与4-异烟酰胺基哌啶-1-羧酸叔丁酯相同的合成方法，以4-(2-甲苯磺酰基亚苄基)哌啶-1-甲酸叔丁酯和2-吡啶甲醛为原料，得淡黄色油状物249mg，收率63％。 1H NMR(300MHz,DMSO-d 6)δ7.74-7.70(m,2H),7.40-7.37(m,2H),3.41-3.37(m,4H),2.38-2.33(m,4H),2.23-2.19(m,1H),1.42(s,9H).
哌啶-4-基(吡啶-2-基)甲酮
将4-吡啶甲酸叔丁酯-1-羧酸叔丁酯溶于HCl/EA中，室温搅拌半小时，抽滤，干燥得浅黄色固体172mg，收率88％。 1H NMR(400MHz,DMSO-d 6)δ8.77-8.75(m,1H),8.08-8.00(m,2H),7.73-7.70(m,1H),4.07(tt,J＝11.4,3.7Hz,1H),3.29(dt,J＝12.8,3.3Hz,2H),3.03(dtd,J＝12.7,10.0,2.8Hz,2H),2.00(dd,J＝14.1,3.6Hz,2H),1.87-1.76(m,2H)ppm.
(5-氯-1-甲基-1H-吲哚-2-基)(4-吡啶啉基哌啶-1-基)甲酮(I-3)
Figure PCTCN2022120795-appb-000016
采用与(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮相同的合成方法，以为哌啶-4-基(吡啶-2-基)甲酮和5-氯-1-甲基-1H-吲哚-2-羧酸原料，得浅黄色固体53mg，收率29％。 1H NMR(400MHz,DMSO-d 6)δ8.77(ddd,J＝4.7,1.7,1.0Hz,1H),8.06-7.96(m,2H),7.69(ddd,J＝7.3,4.7,1.5Hz,1H),7.66(d,J＝2.0Hz,1H),7.56(d,J＝8.8Hz,1H),7.25(dd,J＝8.8,2.1Hz,1H),6.65(d,J＝0.8Hz,1H),4.55(s,1H),4.20-4.12(m,1H),4.03-3.93(m,1H),3.76(s,3H),3.31-3.06(m,2H),1.95(s,2H),1.63-1.53(m,2H)ppm；HRMS(ESI +):m/z[M+H] +calcd for C 21H 21ClN 3O 2,382.1317；found 382.1365.
(1-(苯并呋喃-2-羰基)哌啶-4-基)(吡啶-2-基)甲酮(I-4)
Figure PCTCN2022120795-appb-000017
采用与(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮相同的合成方法，以苯并呋喃-2-羧酸和哌啶-4-基(吡啶-2-基)甲酮为原料，得白色固体137mg，收率46.44％。 1H NMR(500MHz,Chloroform-d)δ8.64(dd,J＝4.2,1.7Hz,1H),7.87(dd,J＝7.8,1.3Hz,1H),7.79–7.65(m,3H),7.56(d,J＝1.9Hz,1H),7.46–7.37(m,2H),7.32(ddd,J＝7.3,4.2,1.3Hz,1H),3.57(dd,J＝8.5,5.8Hz,2H),3.49(dd,J＝8.5,5.8Hz,2H),3.32(p,J＝6.2Hz,1H),2.15(ddt,J＝21.6,8.6,6.0Hz,4H).
(4-吡啶啉基哌啶)(喹啉-3-基)甲酮(I-5)
Figure PCTCN2022120795-appb-000018
采用与(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮相同的合成方法，以喹啉-3-羧酸和哌啶-4-基(吡啶-2-基)甲酮为原料，得白色固体159mg，收率52.18％。 1H NMR(500MHz,Chloroform-d)δ8.84(d,J＝1.6Hz,1H),8.64(dd,J＝4.2,1.7Hz,1H),8.59(t,J＝1.7Hz,1H),8.01(ddd,J＝8.3,2.3,1.0Hz,1H),7.88(ddd,J＝12.4,7.5,1.2Hz,2H),7.72(td,J＝7.6,1.6Hz,1H),7.65(td,J＝7.5,1.1Hz,1H),7.49(td,J＝8.3,1.4Hz,1H),7.32(ddd,J＝7.3,4.2,1.3Hz,1H),3.64(dd,J＝8.5,5.8Hz,2H),3.59(dd,J＝8.5,5.8Hz,2H),3.34(p,J＝6.2Hz,1H),2.17(dt,J＝8.4,6.0Hz,2H),2.08(dt,J＝8.4,5.9Hz,2H).
吡啶-2-基(1-(喹啉-3-基甲基)哌啶-4-基)甲酮(I-6)
Figure PCTCN2022120795-appb-000019
将哌啶-4-基(吡啶-2-基)甲酮(200mg，1.05mmol，1eq)溶于乙腈中，加入碳酸钾(647mg，4.21mmol，4eq)和碘化钾(388mg，2.10mmol，2eq)，室温搅拌30分钟后加入3-(溴甲基)喹啉(218mg，1.58mmol，1.5eq)，升温至80℃搅拌2.5小时后抽滤，滤液加水后用二氯甲烷(3×30mL)萃取，合并的有机相用10％磷酸二氢钾(3×30mL)洗涤，再用饱和食盐水(3×30mL)洗涤，最后加入无水硫酸钠干燥，减压蒸除溶剂，经柱层析分离纯化得浅黄色固体109mg，收率31％。 1H NMR(300MHz,DMSO-d6)δ8.68(dd,J＝4.2,1.4Hz,1H),8.59(d,J＝1.6Hz,1H),8.04–7.95(m,3H),7.93–7.79(m,2H),7.85–7.75(m,1H),7.62–7.47(m,2H),7.52–7.40(m,1H),3.71(s,1H),3.22(q,J＝6.1Hz,1H),3.02–2.77(m,3H),2.07–1.80(m,4H).
4-(噁唑-2-羰基)哌啶-1-甲酸叔丁酯
将噁唑(284μl，4.32mmol，1.2eq)溶于无水THF中，-40℃下缓慢加入LDA(3.6ml，7.2mmol，2eq)，搅拌30min后加入1-Boc-4-[(甲氧基)甲基氨基甲酰]哌啶(1g，3.6mmol，1eq)的THF溶液，然后升至室温反应过夜。反应结束后，加入饱和氯化铵溶液淬灭，然后用EA萃取3次，合并有机相，再用饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得228mg，收率22％。 1H NMR(400MHz,CDCl 3)δ8.19(d,J＝0.8Hz,1H),7.62(d,J＝0.9Hz,1H),3.84-3.79(m,2H),3.75-3.69(m,2H),3.24-3.19(m,1H),2.14-2.04(m,4H),1.45(s,9H)ppm.
恶唑-2-基(哌啶-4-基)甲酮
将4-(噁唑-2-羰基)哌啶-1-甲酸叔丁酯溶于少量EA中，加入HCl/EA，室温反应30min，有大量白色固体析出，过滤并干燥得白色固体134mg，收率87％。 1H NMR(400MHz,DMSO-d 6)δ9.10(s,1H),8.74(s,1H),3.29-3.23(m,2H),3.11(s,2H),2.99-2.89(m,2H),1.85-1.72(m,4H)ppm.
(5-氯-1-甲基-1H-吲哚-2-基)(4-(恶唑-2-羰基)哌啶-1-基)甲酮(I-7)
Figure PCTCN2022120795-appb-000020
参照(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮的合成方法，得79mg固体，收率23％。 1H NMR(400MHz,DMSO-d 6)δ8.44((d,J＝1.7Hz,1H),7.67-7.65(m,1H),7.59-7.55(m,2H),7.27-7.23(m,1H),6.65(s,1H),4.52(s,1H),4.04-3.93(m,1H),3.76(s,3H),3.73-3.69(m,1H),3.17-3.11(m,2H),2.01-2.00(m,2H),1.66-1.56(m,2H)ppm；HRMS(ESI +):m/z[M+H] +calcd for C 19H 19ClN 3O 3,372.1109；found 372.1164.
4-(噻唑-2-羰基)哌啶-1-甲酸叔丁酯
将噻唑(312μl，4.41mmol，1.2eq)溶于无水THF中，-40℃下缓慢加入LDA(3.6ml， 7.2mmol，2eq)，搅拌30min后加入1-Boc-4-[(甲氧基)甲基氨基甲酰]哌啶(1g，3.67mmol，1eq)的THF溶液，然后升至室温反应过夜。反应结束后，加入饱和氯化铵溶液淬灭，然后用EA萃取3次，合并有机相，再用饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得228mg，收率22％。，得浅黄色油状物595mg，收率56％。 1H NMR(400MHz,CDCl 3)δ7.90(d,J＝4.8Hz,1H),7.62(d,J＝4.6Hz,1H),3.79-3.74(m,2H),3.48-3.43(m,2H),3.27-3.23(m,1H),2.24-2.11(m,4H),1.45(s,9H).
哌啶-4-基(噻唑-2-基)甲酮
将4-(噻唑-2-羰基)哌啶-1-甲酸叔丁酯溶于少量EA中，加入HCl/EA，室温反应30min，有大量白色固体析出，过滤并干燥得白色固体376mg，收率87％。 1H NMR(400MHz,DMSO-d 6)δ9.25(s,1H),8.91(s,1H),3.40(s,1H),3.28-3.22(m,2H),3.01-2.88(m,3H),1.85-1.70(m,4H)ppm.
(5-氯-1-甲基-1H-吲哚-2-基)(4-(噻唑-2-羰基)哌啶-1-基)甲酮(I-8)
Figure PCTCN2022120795-appb-000021
参照(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮的合成方法，得237mg固体，收率47％。 1H NMR(400MHz,DMSO-d6)δ8.25(d,J＝3.0Hz,1H),8.19(d,J＝3.0Hz,1H),7.66(d,J＝2.0Hz,1H),7.56(d,J＝8.8Hz,1H),7.25(dd,J＝8.8,2.0Hz,1H),6.65(d,J＝3.0Hz,1H),4.71–4.35(m,1H),4.21–3.96(m,1H),3.95–3.83(m,1H),3.76(s,3H),3.31–3.00(m,2H),2.16–1.90(m,2H),1.78–1.54(m,2H).
4-(苯并[d]噻唑-2-羰基)哌啶-1-甲酸叔丁酯
采用与4-(噻唑-2-羰基)哌啶-1-甲酸叔丁酯相同的合成方法，以苯并噻唑为原料，得淡黄色固体325mg，收率51％。 1H NMR(300MHz,DMSO-d 6)δ8.33-8.25(m,2H),7.73-7.64(m,2H),4.05(d,J＝13.2Hz,2H),3.90(tt,J＝11.4,3.6Hz,1H),2.97(s,2H),2.04-1.99(m,2H),1.65-1.45(m,2H),1.44(s,9H)ppm.
苯并[d]噻唑-2-基(哌啶-4-基)甲酮
将苯并[d]噻唑-2-基(哌啶-4-基)甲酮溶于少量EA中，加入HCl/EA，室温反应30min，有大量白色固体析出，过滤并干燥得白色固体256mg，收率97％。 1H NMR(300MHz,DMSO-d 6)δ8.33-8.23(m,2H),7.74-7.65(m,2H),4.02(tt,J＝11.2,3.7Hz,1H),3.35(s,2H),3.18-3.06(m,2H),2.22-2.17(m,2H),2.01-1.87(m,2H)ppm.
苯并[d]噻唑-2-基(1-(5-氯-1-甲基-1H-吲哚-2-羰基)哌啶-4-基)甲酮(I-9)
Figure PCTCN2022120795-appb-000022
参照(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮的合成方法，得24mg固体，收率30％。 1H NMR(300MHz,DMSO-d 6)δ8.32-8.27(m,2H),7.76-7.57(m,4H),7.29-7.25(m,1H),6.69(s,1H),4.59(s,1H),4.08-4.06(m,2H),3.79(s,3H),3.42-3.39(m,2H),2.15(s,2H),1.76-1.69(m,2H)ppm；HRMS(ESI +):m/z[M+H] +calcd for C 23H 21ClN 3O 2S,438.1038；found 438.1118.
5-苯恶唑
将苯甲醛(1g，9.42mmol，1eq)溶于甲醇中，加入对甲基苯磺酰异腈(2.023g，10.362mmol，1.1eq)和K 2CO 3(2.598g，18.8mmol，2eq)，80℃下回流反应1.5h。反应结束后，减压浓缩除去甲醇，再用DCM溶解过滤掉不溶物K 2CO 3，滤液减压浓缩后再通过柱层析纯化得固体1.03g，收率74％。 1H NMR(300MHz,DMSO-d 6)δ8.44(s,1H),7.74-7.71(m,2H),7.69(s,1H),7.50-7.45(m,2H),7.40-7.34(m,1H)ppm.
4-(5-苯基恶唑-2-羰基)哌啶-1-甲酸叔丁酯
将5-苯恶唑(320mg，2.208mmol，1.2eq)溶于无水THF中，-40℃下缓慢加入LDA(1.1ml，2.208mmol，1.2eq)，搅拌30min后加入1-Boc-4-[(甲氧基)甲基氨基甲酰]哌啶(500mg，1.84mmol，1eq)的THF溶液，然后升至室温反应过夜。反应结束后，加入饱和氯化铵溶液淬灭，然后用EA萃取3次，合并有机相，再用饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得固体325mg，收率37％。 1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.89–7.82(m,2H),7.59–7.51(m,2H),7.51–7.44(m,1H),4.00(d,J＝13.0Hz,2H),3.59(tt,J＝11.5,3.6Hz,1H),2.90(s,2H),1.92(dd,J＝13.7,3.5Hz,2H),1.54–1.43(m,2H),1.43–1.39(m,9H).
(5-苯基恶唑-2-基)(哌啶-4-基)甲酮
将4-(5-苯基恶唑-2-羰基)哌啶-1-甲酸叔丁酯溶于氯化氢-二氧六环溶液，室温反应30min，有大量白色固体析出，过滤并干燥得固体152mg，收率77％。 1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.90–7.83(m,2H),7.59–7.45(m,3H),3.72(tt,J＝11.3,3.6Hz,1H),3.33(d,J＝12.8Hz,2H),3.05(q,J＝12.3,11.9Hz,2H),2.11(dd,J＝14.4,3.6Hz,2H),1.87(q,J＝11.1Hz,2H).
(5-氯-1-甲基-1H-吲哚-2-基)(4-(5-苯基恶唑-2-羰基)哌啶-1-基)甲酮(I-10)
Figure PCTCN2022120795-appb-000023
参照(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮的合成方法，得18mg固体，收率24％。 1H NMR(400MHz,DMSO-d6)δ8.08(d,J＝4.1Hz,1H),7.91–7.83(m,2H),7.69–7.66(m,1H),7.60–7.52(m,3H),7.52–7.49(m,2H),7.31–7.19(m,1H),6.67(s,1H),4.55(s,1H),4.05(s,1H),3.77(s,4H),3.71(s,1H),3.25–3.04(m,2H),2.15–1.92(m,2H),1.70–1.57(m,2H).
2-苯基-1,3,4-恶二唑
将苯甲酰肼(1g，7.345mmol，1eq)溶于原甲酸三甲酯中，加入对甲基苯磺酸(126mg，0.7345mmol，0.1eq)，120℃下回流反应1.5h。反应结束后，直接柱层析纯化得固体1.05g，收率98％。 1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),7.91–7.86(m,2H),7.68–7.53(m,3H).
4-(5-苯基-1,3,4-恶二唑-2-羰基)哌啶-1-甲酸叔丁酯
将2-苯基-1,3,4-恶二唑(323mg，2.21mmol，1.2eq)溶于无水THF中，-40℃下缓慢加入n-BuLi(0.88ml，2.21mmol，1.2eq)，搅拌30min后加入1-Boc-4-[(甲氧基)甲基氨基甲酰]哌啶(500mg，1.84mmol，1eq)的THF溶液，然后升至室温反应过夜。反应结束后，加入饱和氯化铵溶液淬灭，然后用EA萃取3次，合并有机相，再用饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得固体227mg，收率34％。 1H NMR(300MHz,DMSO-d6)δ8.18–8.09(m,2H),7.80–7.62(m,3H),4.08–3.98(m,2H),3.64(tt,J＝11.4,3.6Hz,1H),2.95(d,J＝14.8Hz,2H),2.03(d,J＝13.0Hz,2H),1.54(tt,J＝12.1,6.1Hz,2H),1.44(s,9H).
(5-苯基-1,3,4-恶二唑-2-基)(哌啶-4-基)甲酮
将227mg4-(5-苯基-1,3,4-恶二唑-2-羰基)哌啶-1-甲酸叔丁酯溶于氯化氢-二氧六环溶液，室温反应30min，有大量白色固体析出，过滤并干燥得固体120mg，收率65％。 1H NMR(400MHz,DMSO-d6)δ9.41–9.10(m,2H),8.11(dd,J＝5.9,3.8Hz,1H),7.68(dtd,J＝14.9,7.3,2.2Hz,2H),3.71–3.67(m,3H),3.28–3.21(m,1H),3.10(s,1H),2.93(d,J＝11.9Hz,1H),2.17(dd,J＝14.3,3.7Hz,1H),2.03–1.88(m,1H),1.79(td,J＝12.1,11.3,5.9Hz,2H).
(5-氯-1-甲基-1H-吲哚-2-基)(4-(5-苯基-1,3,4-恶二唑-2-羰基)哌啶-1-基)甲酮(I-11)
Figure PCTCN2022120795-appb-000024
参照(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮的合成方法，得16mg固体，收率21％。 1H NMR(300MHz,DMSO-d6)δ8.14(dd,J＝7.2,2.3Hz,2H),7.78–7.63(m,4H),7.59(dd,J＝8.9,2.4Hz,1H),7.27(dt,J＝8.8,2.5Hz,1H),6.69(s,1H),4.71–4.36(m,1H),4.28–3.98(m,1H),3.79(d,J＝2.5Hz,4H),3.18-3.01(m,2H),2.28–1.99(m,2H),1.85–1.56(m,2H).
2-(吡啶-3-基)-1,3,4-恶二唑
将3-吡啶甲酰肼(1g，7.3mmol，1eq)溶于原甲酸三甲酯中，加入对甲基苯磺酸(126mg，0.73mmol，0.1eq)，120℃下回流反应1.5h。反应结束后，加EA稀释，再分别用水和饱和食盐水洗涤3次，无水硫酸钠干燥，减压浓缩得白色固体915mg，收率85％。 1H NMR(300MHz,DMSO-d 6)δ9.47(d,J＝3.0Hz,1H),9.22(d,J＝2.9Hz,1H),8.84(ddd,J＝5.0,3.5,1.7Hz,1H),8.43(ddt,J＝7.8,3.8,1.9Hz,1H),7.68(dt,J＝8.0,3.8Hz,1H)ppm.
4-(羟基(5-(吡啶-3-基)-1,3,4-恶二唑-2-基)甲基)哌啶-1-甲酸叔丁酯
将2-(吡啶-3-基)-1,3,4-恶二唑(250mg，1.7mmol，1eq)溶于无水THF中，-78℃下缓慢加入LDA(1.3ml，2.55mmol，1.5eq)，搅拌30min后加入1-Boc-4-哌啶甲醛(362mg，1.7mmol，1eq)的THF溶液，然后升至室温，继续反应3h。反应结束后加入饱和氯化铵溶液淬灭，再用EA萃取3次，合并有机相，接着用饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得淡黄色固体290mg，收率47％。 1H NMR(300MHz,DMSO-d 6)δ9.20(dd,J＝2.3,0.9Hz,1H),8.84(dd,J＝4.8,1.6Hz,1H),8.40(dt,J＝8.0,2.0Hz,1H),7.68(ddd,J＝7.9,4.9,0.9Hz,1H),6.20(d,J＝5.6Hz,1H),4.72(dd,J＝7.3,5.6Hz,1H),3.99(t,J＝16.7Hz,2H),2.72(s,2H),2.06(ddt,J＝15.3,7.8,3.4Hz,1H),1.48(s,2H),1.41(s,9H),1.30-1.13(m,2H)ppm.
4-(5-(吡啶-3-基)-1,3,4-恶二唑-2-羰基)哌啶-1-甲酸叔丁酯
将4-(羟基(5-(吡啶-3-基)-1,3,4-恶二唑-2-基)甲基)哌啶-1-甲酸叔丁酯(270mg，0.75mmol，1eq)溶液DCM中，加入戴斯马丁氧化剂(636mg，1.5mmol，2eq)，室温反应30min。反应结束后加入饱和碳酸氢钠溶液搅拌5min，随后用EA萃取3次，合并有机相，再分别用饱和碳酸氢钠和饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得淡黄色固体182mg，收率68％。 1H NMR(300MHz,DMSO-d 6)δ9.28(dd,J＝2.3,0.9Hz,1H),8.90(dd,J＝4.8,1.7Hz,1H),8.50(dt,J＝8.1,1.9Hz,1H),8.06-7.96(m,1H),4.03(d,J＝13.3Hz,2H),3.65(tt,J＝11.4,3.7Hz,1H),2.97(s,2H),2.06-2.00(m,2H),1.65-1.48(m,2H),1.44(s,9H),1.42-1.41(m,2H)ppm.
哌啶-4-基(5-(吡啶-3-基)-1,3,4-恶二唑-2-基)甲酮
将182mg4-(5-(吡啶-3-基)-1,3,4-恶二唑-2-羰基)哌啶-1-甲酸叔丁酯溶于氯化氢-二氧六环溶液，室温反应30min，有大量白色固体析出，过滤并干燥得到白色固体111mg，收率84％。 1H NMR(300MHz,DMSO-d 6)δ9.33(d,J＝2.3Hz,1H),8.94(dd,J＝4.9,1.6Hz,1H),8.58(dt,J＝8.1,2.0Hz,1H),7.79(dd,J＝8.1,4.9Hz,1H),3.78(tt,J＝11.2,3.7Hz,1H),3.41-3.30(m,2H),3.15-3.06(m,2H),2.21(dd,J＝14.5,3.6Hz,2H),1.96(qd,J＝11.6,6.0Hz,2H)ppm.
(5-氯-1-甲基-1H-吲哚-2-基)(4-(5-(吡啶-3-基)-1,3,4-恶二唑-2-羰基)哌啶-1-基)甲酮(I-12)
Figure PCTCN2022120795-appb-000025
参照(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮的合成方法，得白色固体18mg，收率11.7％。 1H NMR(400MHz,DMSO-d6)δ9.27(dd,J＝2.3,0.9Hz,1H),8.88(dd,J＝4.8,1.7Hz,1H),8.48(dt,J＝8.1,1.9Hz,1H),7.72–7.66(m,2H),7.57(d,J＝8.8Hz,1H),7.25(dd,J＝8.8,2.1Hz,1H),6.67(s,1H),4.67–4.43(m,1H),4.27–3.93(m,1H),3.84–3.79(m,1H),3.77(s,3H),3.28–3.08(m,2H),2.28–1.95(m,2H),1.83–1.63(m,2H).
2-(3-氯苯基)-1,3,4-恶二唑
将3-氯苯甲酰肼(1g，7.3mmol，1eq)溶于原甲酸三甲酯中，加入对甲基苯磺酸(126mg，0.73mmol，0.1eq)，120℃下回流反应1.5h。反应结束后，加EA稀释，再分别用水和饱和食盐水洗涤3次，无水硫酸钠干燥，减压浓缩得白色固体915mg，收率85％。 1H NMR(300MHz,DMSO-d 6)δ9.47(d,J＝3.0Hz,1H),9.22(d,J＝2.9Hz,1H),8.84(ddd,J＝5.0,3.5,1.7Hz,1H),8.43(ddt,J＝7.8,3.8,1.9Hz,1H),7.68(dt,J＝8.0,3.8Hz,1H)ppm.
4-((5-(3-氯苯基)-1,3,4-恶二唑-2-基)(羟基)甲基)哌啶-1-羧酸叔丁酯
将2-(3-氯苯基)-1,3,4-恶二唑(250mg，1.7mmol，1eq)溶于无水THF中，-78℃下缓慢加入LDA(1.3ml，2.55mmol，1.5eq)，搅拌30min后加入1-Boc-4-哌啶甲醛(362mg，1.7mmol，1eq)的THF溶液，然后升至室温，继续反应3h。反应结束后加入饱和氯化铵溶液淬灭，再用EA萃取3次，合并有机相，接着用饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得淡黄色固体290mg，收率47％。 1H NMR(300MHz,DMSO-d 6)δ9.20(dd,J＝2.3,0.9Hz,1H),8.84(dd,J＝4.8,1.6Hz,1H),8.40(dt,J＝8.0,2.0Hz,1H),7.68(ddd,J＝7.9,4.9,0.9Hz,1H),6.20(d,J＝5.6Hz,1H),4.72(dd,J＝7.3,5.6Hz,1H),3.99(t,J＝16.7Hz,2H),2.72(s,2H),2.06(ddt,J＝15.3,7.8,3.4Hz,1H),1.48(s,2H),1.41(s,9H),1.30-1.13(m,2H)ppm.
4-(5-(3-氯苯基)-1,3,4-恶二唑-2-羰基)哌啶-1-羧酸叔丁酯
将4-((5-(3-氯苯基)-1,3,4-恶二唑-2-基)(羟基)甲基)哌啶-1-羧酸叔丁酯(270mg，0.75mmol，1eq)溶液DCM中，加入戴斯马丁氧化剂(636mg，1.5mmol，2eq)，室温反应30min。反应结束后加入饱和碳酸氢钠溶液搅拌5min，随后用EA萃取3次，合并有机相，再分别用饱和碳酸氢钠和饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得淡黄色固体182mg，收率68％。 1H NMR(300MHz,DMSO-d 6)δ9.28(dd,J＝2.3,0.9Hz,1H),8.90(dd,J＝4.8,1.7Hz,1H),8.50(dt,J＝8.1,1.9Hz,1H),8.06-7.96(m,1H),4.03(d,J＝13.3Hz,2H),3.65(tt,J＝11.4,3.7Hz,1H),2.97(s,2H),2.06-2.00(m,2H),1.65-1.48(m,2H),1.44(s,9H),1.42-1.41(m,2H)ppm.
(5-(3-氯苯基)-1,3,4-恶二唑-2-基)(哌啶-4-基)甲酮
将182mg 4-(5-(3-氯苯基)-1,3,4-恶二唑-2-羰基)哌啶-1-羧酸叔丁酯溶于氯化氢-二氧六环溶液，室温反应30min，有大量白色固体析出，过滤并干燥得到白色固体111mg，收率84％。 1H NMR(300MHz,DMSO-d 6)δ9.33(d,J＝2.3Hz,1H),8.94(dd,J＝4.9,1.6Hz,1H),8.58(dt,J＝8.1,2.0Hz,1H),7.79(dd,J＝8.1,4.9Hz,1H),3.78(tt,J＝11.2,3.7Hz,1H),3.41-3.30(m,2H),3.15-3.06(m,2H),2.21(dd,J＝14.5,3.6Hz,2H),1.96(qd,J＝11.6,6.0Hz,2H)ppm.
(5-氯-1-甲基-1H-吲哚-2-基)(4-(5-(3-氯苯基)-1,3,4-恶二唑-2-羰基)哌啶-1-基)甲酮(I-13)
Figure PCTCN2022120795-appb-000026
参照(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮的合成方法，得白色固 体18mg，收率11.7％。 1H NMR(400MHz,DMSO-d6)δ9.27(dd,J＝2.3,0.9Hz,1H),8.88(dd,J＝4.8,1.7Hz,1H),8.48(dt,J＝8.1,1.9Hz,1H),7.72–7.66(m,2H),7.57(d,J＝8.8Hz,1H),7.25(dd,J＝8.8,2.1Hz,1H),6.67(s,1H),4.67–4.43(m,1H),4.27–3.93(m,1H),3.84–3.79(m,1H),3.77(s,3H),3.28–3.08(m,2H),2.28–1.95(m,2H),1.83–1.63(m,2H).
6-氯吡啶-2-羧酸酰肼
将6-氯-2-吡啶羧酸甲酯(2g，11.66mmol，1eq)溶于甲醇中，加入水合肼(0.7g，14mmol，1.2eq),室温下搅拌20min，减压蒸馏除去溶剂甲醇，加入MTBE搅拌15min，抽滤，得到白色粉末状固体，真空干燥箱干燥，称量得白色粉末状固体1.32g，收率66％。 1H NMR(300MHz,DMSO)δ9.96(s,1H),8.07(t,J＝7.7Hz,1H),7.98(dd,J＝7.6,1.1Hz,1H),7.73(dd,J＝7.8,1.1Hz,1H),4.65(s,2H).
2-(3-氯吡啶-2-基)-1,3,4-恶二唑
将6-氯吡啶-2-羧酸酰肼(1g，5.83mmol，1eq)溶于原甲酸三甲酯中，加入对甲基苯磺酸(100mg，0.58mmol，0.1eq)，120℃下回流反应1.5h。反应结束后，加EA稀释，再分别用水和饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得白色粉末状固体812mg，收率76.73％。 1H NMR(300MHz,DMSO)δ9.49(s,1H),8.28–8.02(m,2H),7.82(dd,J＝7.9,1.0Hz,1H).
4-(羟基(5-(3-氯吡啶-2-基)-1,3,4-恶二唑-2-基)甲基)哌啶-1-甲酸叔丁酯
将2-(3-氯吡啶-2-基)-1,3,4-恶二唑(251mg，1.38mmol，1eq)溶于无水THF中，-78℃下缓慢加入LDA(1ml，2.07mmol，1.5eq)，搅拌30min后加入1-Boc-4-哌啶甲醛(295mg，1.38mmol，1eq)的THF溶液，然后升至室温，继续反应3h。反应结束后加入饱和氯化铵溶液淬灭，再用EA萃取3次，合并有机相，接着用饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得固体232.5mg，收率42.60％。 1H NMR(400MHz,DMSO-d6)δ8.20(dd,J＝7.7,1.0Hz,1H),8.15–8.02(m,1H),7.79(dd,J＝8.0,0.9Hz,1H),6.22(d,J＝5.7Hz,1H),4.71(dd,J＝7.3,5.8Hz,1H),4.49–3.94(m,2H),3.24(t,J＝5.8Hz,2H),2.09–1.83(m,1H),1.78–1.50(m,2H),1.38(s,9H),1.27–0.93(m,2H).
哌啶-4-基(5-(3-氯吡啶吡啶-2-基)-1,3,4-恶二唑-2-基)甲酮
将4-(羟基(5-(3-氯吡啶-2-基)-1,3,4-恶二唑-2-基)甲基)哌啶-1-甲酸叔丁酯(220mg，0.56mmol，1eq)溶液DCM中，加入戴斯马丁氧化剂(474mg，1.12mmol，2eq)，室温反应30min。反应结束后加入饱和碳酸氢钠溶液搅拌5min，随后用EA萃取3次，合并有机相，再分别用饱和碳酸氢钠和饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得白色粉末状固体。将该固体溶于氯化氢-二氧六环溶液，室温反应30min，有固体析出，过滤并干燥得到淡黄色固体47.7mg，收率26.01％。 1H NMR(300MHz,DMSO-d6)δ9.04(s,1H),8.84(s,1H),8.21(d,J＝7.6Hz,1H),8.08(t,J＝7.8Hz,1H),7.77(d,J＝8.0Hz,1H),3.65(tt,J＝11.5,3.8Hz,1H),3.22(s,2H),2.99(q,J＝11.7Hz,2H),2.08(d,J＝13.3Hz,2H),1.88–1.70(m,2H).
(5-氯-1-甲基-1H-吲哚-2-基)(4-(5-(3-氯吡啶-2-基)-1,3,4-恶二唑-2-羰基)哌啶-1-基)甲 酮(I-14)
Figure PCTCN2022120795-appb-000027
参照(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮的合成方法，得白色固体43mg，收率64.95％。 1H NMR(400MHz,DMSO)δ8.31(d,J＝7.7Hz,1H),8.17(t,J＝7.9Hz,1H),7.86(d,J＝8.0Hz,1H),7.67(d,J＝2.1Hz,1H),7.57(d,J＝8.8Hz,1H),7.29–7.16(m,1H),6.67(s,1H),4.47(d,J＝14.7Hz,1H),3.77(s,3H),2.07(d,J＝58.7Hz,2H),1.69(qd,J＝12.8,12.0,4.0Hz,2H),1.33–1.16(m,4H).
2-(呋喃-2-基)-1,3,4-恶二唑
将2-呋喃甲酰肼(1.5g，11.89mmol，1eq)溶于原甲酸三甲酯中，加入对甲基苯磺酸(200mg，1.2mmol，0.1eq)，120℃下回流反应1.5h。反应结束后，加EA稀释，再分别用水和饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得无色油状液体1.3g，收率80.3％。 1H NMR(400MHz,DMSO)δ9.33(s,1H),8.07(s,1H),7.39(d,J＝3.6Hz,1H),6.81(d,J＝3.0Hz,1H).
4-(羟基(5-(呋喃-2-基)-1,3,4-恶二唑-2-基)甲基)哌啶-1-甲酸叔丁酯
将2-(呋喃-2-基)-1,3,4-恶二唑1.3g，9.55mmol，1eq)溶于无水THF中，-78℃下缓慢加入LDA(7ml，14.33mmol，1.5eq)，搅拌30min后加入1-Boc-4-哌啶甲醛(2g，9.55mmol，1eq)的THF溶液，然后升至室温，继续反应3h。反应结束后加入饱和氯化铵溶液淬灭，再用EA萃取3次，合并有机相，接着用饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得黄色泡沫状固体918.8mg，收率27.53％。 1H NMR(300MHz,DMSO)δ8.03(d,J＝1.7Hz,1H),7.32(d,J＝3.5Hz,1H),6.77(dd,J＝3.5,1.8Hz,1H),6.14(d,J＝5.6Hz,1H),4.64(dd,J＝7.3,5.5Hz,1H),4.07–3.82(m,2H),2.75–2.44(m,2H),1.97(s,1H),1.96–1.74(m,2H),1.36(s,9H),1.20–1.10(m,2H).
4-(5-(呋喃-2-基)-1,3,4-恶二唑-2-羰基)哌啶-1-甲酸叔丁酯
将4-(羟基(5-(呋喃-2-基)-1,3,4-恶二唑-2-基)甲基)哌啶-1-甲酸叔丁酯(918mg，2.63mmol，1eq)溶液DCM中，加入戴斯马丁氧化剂(2.23g，5.26mmol，2eq)，室温反应30min。反应结束后加入饱和碳酸氢钠溶液搅拌5min，随后用EA萃取3次，合并有机相，再分别用饱和碳酸氢钠和饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得白色粉末状固体663mg，收率72.62％。 1H NMR(400MHz,DMSO)δ8.16(dd,J＝1.8,0.8Hz,1H),7.57(dd,J＝3.6,0.8Hz,1H),6.86(dd,J＝3.6,1.8Hz,1H),4.01(dd,J＝15.0,9.9Hz,2H),3.57(tt,J＝11.3,3.6Hz,1H),2.92(s,2H),2.03–1.94(m,2H),1.59–1.43(m,2H),1.41(s,9H).
哌啶-4-基(5-(呋喃-2-基)-1,3,4-恶二唑-2-基)甲酮
将209mg4-(5-(呋喃-2-基)-1,3,4-恶二唑-2-羰基)哌啶-1-甲酸叔丁酯溶于氯化氢-二氧六环溶液，室温反应30min，有大量淡黄色固体析出，过滤并干燥得固体170mg，收率99.59％。 1H NMR(400MHz,DMSO)δ9.07(d,J＝71.9Hz,2H),8.17(d,J＝1.7Hz,1H),7.59(dd,J＝3.6,0.7Hz,1H),6.87(dd,J＝3.6,1.8Hz,1H),3.71(tt,J＝11.2,3.6Hz,1H),3.33(d,J＝12.9Hz,2H),3.13–3.00(m,2H),2.21–2.12(m,2H),1.96–1.81(m,2H).
(5-氯-1-甲基-1H-吲哚-2-基)(4-(5-(呋喃-2-基)-1,3,4-恶二唑-2-羰基)哌啶-1-基)甲酮(I-15)
Figure PCTCN2022120795-appb-000028
参照(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮的合成方法，得白色固体70.1mg，收率75.46％。 1H NMR(400MHz,DMSO)δ8.17(d,J＝1.7Hz,1H),7.67(d,J＝2.1Hz,1H),7.58(s,1H),7.57(d,J＝13.7Hz,1H),7.29–7.18(m,1H),6.87(dd,J＝3.6,1.7Hz,1H),6.67(s,1H),3.76(s,3H),3.73(d,J＝11.9Hz,1H),3.15(s,2H),2.11(s,2H),1.67(qd,J＝11.6,3.9Hz,2H),1.38–1.25(m,2H).
2-(噻吩-2-基)-1,3,4-恶二唑
将2-噻吩甲酰肼(1.4g，9.85mmol，1eq)溶于原甲酸三甲酯中，加入对甲基苯磺酸(170mg，0.99mmol，0.1eq)，120℃下回流反应1.5h。反应结束后，加EA稀释，再分别用水和饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得无色油状液体1.2g，收率80.08％。 1H NMR(400MHz,DMSO)δ9.30(s,1H),7.96(dd,J＝5.0,1.2Hz,1H),7.91–7.82(m,1H),7.30(dd,J＝5.0,3.7Hz,1H).
4-(羟基(5-(噻吩-2-基)-1,3,4-恶二唑-2-基)甲基)哌啶-1-甲酸叔丁酯
将2-(噻吩-2-基)-1,3,4-恶二唑(1.2g，7.89mmol，1eq)溶于无水THF中，-78℃下缓慢加入LDA(6ml，11.84mmol，1.5eq)，搅拌30min后加入1-Boc-4-哌啶甲醛(1.7g，7.89mmol，1eq)的THF溶液，然后升至室温，继续反应3h。反应结束后加入饱和氯化铵溶液淬灭，再用EA萃取3次，合并有机相，接着用饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得黄色泡沫状固体552.5mg，收率19.17％。 1H NMR(400MHz,DMSO)δ7.95(dd,J＝5.0,1.2Hz,1H),7.82(dd,J＝3.7,1.2Hz,1H),7.29(dd,J＝5.0,3.7Hz,1H),6.16(d,J＝5.6Hz,1H),4.65(dd,J＝7.4,5.6Hz,1H),4.06–3.90(m,2H),2.69(s,2H),2.01(ddd,J＝11.8,5.6,2.3Hz,1H),1.93–1.41(m,1H),1.38(s,9H),1.18(dtt,J＝20.5,12.6,6.2Hz,2H).
4-(5-(噻吩-2-基)-1,3,4-恶二唑-2-羰基)哌啶-1-甲酸叔丁酯
将4-(羟基(5-(噻吩-2-基)-1,3,4-恶二唑-2-基)甲基)哌啶-1-甲酸叔丁酯(552mg，1.51mmol，1eq)溶液DCM中，加入戴斯马丁氧化剂(1.3g，3.02mmol，2eq)，室温反应30min。反应结束后加入饱和碳酸氢钠溶液搅拌5min，随后用EA萃取3次，合并有机相，再分别用饱和碳酸氢钠和饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得黄色固体496.6mg，收率90.46％ 1H NMR(400MHz,DMSO)δ8.07(dd,J＝5.0,1.2Hz,1H),7.99(dd,J＝3.8,1.2Hz, 1H),7.35(dd,J＝5.0,3.8Hz,1H),3.99(d,J＝13.2Hz,2H),3.57(dq,J＝11.3,3.9Hz,2H),3.17(s,1H),2.03–1.94(m,2H),1.50(td,J＝12.4,4.2Hz,2H),1.41(s,9H).
哌啶-4-基(5-(噻吩-2-基)-1,3,4-恶二唑-2-基)甲酮
将277mg4-(5-(噻吩-2-基)-1,3,4-恶二唑-2-羰基)哌啶-1-甲酸叔丁酯溶于氯化氢-二氧六环溶液，室温反应30min，有大量淡黄色固体析出，过滤并干燥得淡黄色固体195mg，收率85.35％ 1H NMR(400MHz,DMSO)δ9.13(s,1H),8.94(s,1H),8.09(dd,J＝5.0,1.2Hz,1H),8.00(dd,J＝3.8,1.2Hz,1H),7.36(dd,J＝5.0,3.8Hz,1H),3.71(tt,J＝11.2,3.6Hz,1H),3.31(s,2H),3.18–2.97(m,2H),2.16(dd,J＝14.2,3.6Hz,2H),2.02–1.81(m,2H).
(5-氯-1-甲基-1H-吲哚-2-基)(4-(5-(呋喃-2-基)-1,3,4-恶二唑-2-羰基)哌啶-1-基)甲酮(I-16)
Figure PCTCN2022120795-appb-000029
参照(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮的合成方法，得淡黄色固体90mg，收率58.69％ 1H NMR(400MHz,DMSO)δ8.08(dd,J＝5.0,1.2Hz,1H),8.00(dd,J＝3.8,1.2Hz,1H),7.67(d,J＝2.0Hz,1H),7.57(d,J＝8.8Hz,1H),7.35(dd,J＝5.0,3.7Hz,1H),7.29–7.16(m,1H),6.67(d,J＝0.9Hz,1H),4.51–4.03(m,2H),3.76(s,3H),3.75–3.65(m,1H),3.14(s,1H),2.11(s,2H),1.74–1.59(m,2H).
6-甲氧基吡啶-2-羧酸酰肼
将6-甲氧基-2-吡啶羧酸甲酯(1.04g，6.22mmol，1eq)溶于甲醇中，加入水合肼(374mg，7.46mmol，1.2eq),室温下搅拌20min，减压蒸馏除去溶剂甲醇，加入MTBE搅拌15min，抽滤，得到白色粉末状固体，真空干燥箱干燥，称量得白色粉末状固体914mg，收率87.88％。 1H NMR(400MHz,DMSO)δ9.75(d,J＝16.0Hz,1H),7.90–7.77(m,1H),7.55(dt,J＝17.7,6.8Hz,1H),6.97(q,J＝9.1,8.5Hz,1H),4.57(t,J＝10.4Hz,2H),4.04–3.84(m,3H).
2-(3-甲氧基吡啶-2-基)-1,3,4-恶二唑
将6-甲氧基吡啶-2-羧酸酰肼(893mg，5.34mmol，1eq)溶于原甲酸三甲酯中，加入对甲基苯磺酸(92mg，0.53mmol，0.1eq)，120℃下回流反应1.5h。反应结束后，加EA稀释，再分别用水和饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得白色粉末状固体796.7mg，收率84.18％ 1H NMR(400MHz,DMSO)δ9.40(s,1H),7.95(dd,J＝8.3,7.3Hz,1H),7.81(dd,J＝7.3,0.8Hz,1H),7.09(dd,J＝8.4,0.8Hz,1H),3.95(s,3H).
4-(羟基(5-(3-甲氧基吡啶-2-基)-1,3,4-恶二唑-2-基)甲基)哌啶-1-甲酸叔丁酯
将2-(3-甲氧基吡啶-2-基)-1,3,4-恶二唑251mg，1.42mmol，1eq)溶于无水THF中，-78℃下缓慢加入LDA(1.4ml，2.84mmol，2eq)，搅拌30min后加入1-Boc-4-哌啶甲醛(302mg，1.42mmol，1eq)的THF溶液，然后升至室温，继续反应3h。反应结束后加入饱和氯化铵溶液淬灭，再用EA萃取3次，合并有机相，接着用饱和食盐水洗涤3次，无水硫酸钠干燥， 最后柱层析纯化得黄色油状液滴248.5mg，收率44.92％ 1H NMR(400MHz,DMSO)δ7.94(dt,J＝8.6,7.0Hz,1H),7.77(d,J＝7.3Hz,1H),7.09(d,J＝8.3Hz,1H),6.18(d,J＝5.6Hz,1H),4.74–4.62(m,1H),4.47(t,J＝5.3Hz,2H),3.92(s,3H),3.24(t,J＝5.7Hz,2H),1.87(d,J＝13.3Hz,1H),1.66–1.57(m,2H),1.39(d,J＝1.9Hz,9H),1.27–1.20(m,2H).
4-(5-(3-甲氧基吡啶-2-基)-1,3,4-恶二唑-2-羰基)哌啶-1-甲酸叔丁酯
将4-(羟基(5-(3-甲氧基吡啶-2-基)-1,3,4-恶二唑-2-基)甲基)哌啶-1-甲酸叔丁酯(220mg，0.62mmol，1eq)溶液DCM中，加入戴斯马丁氧化剂(522mg，1.24mmol，2eq)，室温反应30min。反应结束后加入饱和碳酸氢钠溶液搅拌5min，随后用EA萃取3次，合并有机相，再分别用饱和碳酸氢钠和饱和食盐水洗涤3次，无水硫酸钠干燥，最后柱层析纯化得黄色油状液滴149.1mg，收率62.45％。 1H NMR(400MHz,DMSO)δ7.99(dd,J＝8.3,7.3Hz,1H),7.91(dd,J＝7.4,0.9Hz,1H),7.15(dd,J＝8.3,0.9Hz,1H),3.97(s,3H),3.61(tt,J＝11.4,3.6Hz,1H),2.07–1.96(m,2H),1.83–1.78(m,2H),1.51(qd,J＝12.1,4.5Hz,2H),1.40(d,J＝9.5Hz,9H),1.29–1.23(m,2H).
哌啶-4-基(5-(3-甲氧基吡啶-2-基)-1,3,4-恶二唑-2-基)甲酮
将140mg4-(5-(3-甲氧基吡啶-2-基)-1,3,4-恶二唑-2-羰基)哌啶-1-甲酸叔丁酯溶于氯化氢-二氧六环溶液，室温反应30min，有大量淡黄色固体析出，过滤并干燥得黄色固体112mg，收率95.68％。 1H NMR(400MHz,DMSO)δ9.59(s,1H),9.12(s,1H),8.05–7.96(m,1H),7.92(d,J＝7.2Hz,1H),7.16(d,J＝8.3Hz,1H),3.97(s,3H),3.38–3.20(m,2H),3.15–3.02(m,2H),2.24–2.13(m,2H),2.04–1.97(m,1H),1.91(dtd,J＝15.4,11.9,4.1Hz,2H).
(5-氯-1-甲基-1H-吲哚-2-基)(4-(5-(3-甲氧基吡啶-2-基)-1,3,4-恶二唑-2-羰基)哌啶-1-基)甲酮(I-17)
Figure PCTCN2022120795-appb-000030
参照(5-氯-1-甲基-1H-吲哚-2-基)(4-异烟酰基哌啶-1-基)甲酮的合成方法，得淡黄色固体111.8mg，收率72.75％。 1H NMR(400MHz,DMSO)δ7.98(d,J＝8.0Hz,1H),7.92(d,J＝7.2Hz,1H),7.67(d,J＝2.0Hz,1H),7.56(s,1H),7.49–7.29(m,1H),7.29–7.24(m,1H),6.65(d,J＝18.0Hz,2H),3.97(s,3H),3.77(s,3H),3.28(s,2H),2.90(s,2H),2.69(s,1H),1.69(qd,J＝12.0,4.2Hz,2H),1.60–1.44(m,2H).
(5-氯-1-甲基-1H-吲哚-2-基)(4-(5-(3-甲基吡啶基)-1,3,4-恶二唑-2-羰基)哌啶-1-基)甲酮(I-18)
Figure PCTCN2022120795-appb-000031
参照I-1的合成方法，得白色粉末状固体47mg，收率36.37％。 1H NMR(400MHz,DMSO)δ7.75(t,J＝2.9Hz,1H),7.63(d,J＝5.4Hz,1H),7.59–7.52(m,1H),7.33(dd,J＝9.3,4.0Hz,1H),7.24(d,J＝9.0Hz,1H),7.19(d,J＝3.7Hz,1H),6.69–6.58(m,1H),4.02(s,3H),3.76(dd,J＝19.6,3.8Hz,4H),2.58(d,J＝0.7Hz,3H),2.36(p,J＝6.4Hz,1H),1.85–1.48(m,4H).
实施例2：体外FAAH酶抑制活性测试
FAAH可在细胞内水解AEA生成乙醇胺，针对一定量的反应底物，不同的酶活性催化生成不同量的产物，通过检测产物的量可以考察酶活性的高低。本发明依据此原理进行实验设计。依据FAAH试剂盒说明书，稀释一定浓度的FAAH，加入缓冲液、荧光标记的反应底物，然后加入各浓度的化合物，设置空白对照组、JZL-195阳性对照组，反应结束后利用酶标仪进行荧光分析，最后计算其抑制率。
具体结果如表所示：
化合物名称 IC 50
对照组：JZL-195 2.810nm
I-1 27.92μm
I-2 14.24μm
I-3 13.48μm
I-4 10.06μm
I-5 125.0μm
I-6 131.9μm
I-7 77.90nm
I-8 1.029μm
I-9 279.1nm
I-10 112.0nm
I-11 16.81nm
I-12 28.55nm
1-13 89.67nm
I-14 6.21nm
I-15 3.11nm
I-16 12.94nm
I-17 38.12nm
I-18 49.86nm
如上表所示，本发明的化合物具有良好的FAAH抑制活性。
实施例3：
化合物I-11抗神经炎症活性测试
利用经LPS处理的BV2细胞构建神经炎症模型，通过检测炎症因子(TNF-α、IL-1β)的释放水平考察了化合物I-11是否有抑制神经炎症的作用。结果如图1和表1所示，Control 组细胞中，炎症因子(TNF-α、IL-1β)的表达水平极低；经LPS处理后后，TNF-α和IL-1β表达水平均显著升高(p＜0.01)；经LPS处理后后，TNF-α和IL-1β表达水平均显著升高(p＜0.01)；
而给予化合物I-11预处理的细胞，抑制剂1可以剂量依赖性方式降低炎症因子TNF-α和IL-1β的表达。在高浓度下(20μM)，能恢复炎症因子接近正常水平。该实验结果表明，化合物1能够有效抑制LPS诱导的BV2细胞炎症反应，具有较好的抗神经炎症反应，具有进一步开发的潜力。
表1化合物I-11抗炎活性测试
Figure PCTCN2022120795-appb-000032
*p<0.01 vs control group, #p<0.05 vs LPS group, ##p<0.01 vs LPS group.
以小鼠的醋酸扭体实验为疼痛模型测试化合物I-11的镇痛活性，实验动物信息及实验操作如下。
a)实验动物
健康的ICR小鼠，清洁级，体重为20-25g。动物房符合清洁级实验室要求，温度20～22℃，湿度40％～70％，控制光照12小时/黑暗12小时昼夜交替(8:00-20:00光照时间)。小鼠饲养于塑料鼠笼中(体积280×150×180mm)，每笼10只，雌雄分开饲养，自由摄食和饮水，饲料为实验鼠颗粒饲料，饮用水为城市居民饮用水经高温灭菌后使用。动物适应性饲养时间为7天。随动物的所有处理都遵循国际疼痛研究协会伦理委员会的要求。小鼠购入后饲养于动物房中。
b)实验药品及试剂
冰醋酸，生理盐水购于中国药科大学试剂库，I-11为实验室合成化合物(纯度>98％)
c)试验方法
用饱和苦味酸溶液标记小鼠，左前肢为1号，左后肢为2号，右前肢为3号，右后肢为4号，头为5号。头加左前肢为6号，头加左后肢为7号，头加右前肢为8号，头加右后肢为9号，尾为10号。动物分组，每组n＝10，雌雄各半。
本实验采用小鼠扭体实验对样品的镇痛活性进行研究。称取体重为20±2g的昆明种小鼠雌雄各半，随机分4组，每组10只。其中包括样品的高、中、低剂量组和对照组。样品以高(5mg·kg -1)、中(2.5mg·kg -1)、低(1.25mg·kg -1)剂量对小鼠皮下给药，对照组给予等量生理盐水(0.9％NaCl)，给药0.5小时后，每只小鼠腹腔注射0.7％冰醋酸10mL/kg，观察并记录注射冰醋酸后15分钟小鼠的扭体次数及潜伏时间，计算镇痛百分率，进行统计学处理，以T检验判断其显著性。
镇痛百分率(％)＝(对照组平均扭体次数-给药组平均扭体次数)/对照组平均扭体次数
实验结果描述
根据小鼠的醋酸扭体实验，空白对照组，吗啡组、I-11组中小鼠在15分钟内小鼠发生扭体的次数进行对比，5mg·kg -1剂量的I-11对小鼠扭体的抑制率达87.1％，表明化合物I-11具有明显的镇痛活性。
化合物I-11不同浓度对小鼠扭体次数的抑制作用
Figure PCTCN2022120795-appb-000033
化合物I-11抗抑郁活性研究
将体重(180g-200g)雄性SD大鼠随机分成6组，每组8只，分组如下：
正常组；利血平组；阳性对照组(阿米替林，6mg/kg)；I-11低剂量组(3mg/kg)；I-11中剂量组(6mg/kg)；I-11高剂量组(12mg/kg)；
其中正常组正常饲养，其与各组大鼠腹腔注射利血平(0.2mg/kg)，每天一次，持续三天。利血平造模成功后，按组别给予相应的药物。连续给药两周后，依次进行糖水消耗实验，旷场实验和强迫游泳实验。
1.1糖水偏好实验
美国精神疾病协会认为抑郁的重要特征是奖赏反应性的下降，即快感缺失，糖水偏好实验是检测实验动物奖赏反应性的较好的评价指标。
结果如图2和表2所示，模型组与空白组相比较，模型组的蔗糖饮水量显著降低(p<0.01)，说明模型组大鼠出现了明显的快感缺失症状，表明抑郁模型造模成功；阳性对照组(阿米替林)与模型组相比较，治疗组的蔗糖饮水量显著升高，说明阿米替林组的大鼠抑郁症状有明显的缓解。此外，与模型组比较，I-11高剂量组与模型组比较有显著性差异(p<0.01)，其效果略低于阳性对照药阿米替林，表明化合物I-11具有一定的抗抑郁效果。
表-2糖水偏好实验研究
Figure PCTCN2022120795-appb-000034
*p<0.01 vs control group,#p<0.01 vs Model group.
1.2旷场实验
糖水偏好实验结束后，我们对受试动物进行了旷场实验研究。实验结果如图3和表3所示，发现，与正常组相比较，模型组旷场实验大鼠中央停留时间显著增加(p<0.01)；此外 穿越横格数、直立次数、理毛次数均显著减少(p<0.01)。其中，I-11高剂量组在大鼠穿越横格数、直立次数和理毛次数实验中效果与阳性对照阿米替林组相当，表明I-11具有明确的抗抑郁效果。
表3旷场实验研究
Figure PCTCN2022120795-appb-000035
*,P value compared to control group(*P<0.01)； #,P value compared to model group( #P<0.05, ##P<0.01).
1.3强迫游泳实验
强迫游泳实验结果显示，与正常组相比，模型组大鼠强迫游泳不动时间显著延长(p<0.01)。药物干预后，阿米替林组和I-11中、高剂量组均可减少利血平模型大鼠的强迫游泳不动时间(p<0.05)。其中，I-11高剂量(12mg/kg)组效果略低于与阿米替林组(6mg/kg)效果，说明化合物1具有一定的抗抑郁潜力。结果见下表4。
表4强迫游泳实验结果
Figure PCTCN2022120795-appb-000036
*,P value compared to control group(*P<0.01)； #,P value compared to model group( #P<0.05, ##P<0.01).
以上所述仅是本发明的优选实施方式，应当指出：对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

  1. 式I所示的化合物或其药学上可接受的盐：
    Figure PCTCN2022120795-appb-100001
    其中，
    Ar为无取代、单取代或多取代芳杂环；
    R 1表示H或芳环或芳杂环；
    L表示连接链，选自-O-、-S-、-NR 4-、
    Figure PCTCN2022120795-appb-100002
    或-(CH 2) n-,n＝0,1,2,3；R4选自H，C1-C8直链卤代烷烃或卤代支链烷烃基、卤代环烷烃，C1-C8直链烷烃或支链烷烃、环烷烃；
    A为4-7元饱和或不饱和的含有1-2个杂原子N、S或O的杂环；
    R 2、R 3分别独立的表示H或取代基。
  2. 根据权利要求1所述的化合物，其特征在于，Ar为无取代、单取代或多取代芳杂环，其中芳杂环选自：呋喃、噻吩、吡咯、噁唑、异噁唑、咪唑、吡唑、噻唑、异噻唑、三氮唑、1,3,4-噁二唑、1,3,4-噻二唑、1,2,4-噁二唑、1,2,4-噻二唑、吡啶、嘧啶、哒嗪、苯并噁唑、苯并噻唑、嘌呤、喹啉、异喹啉、吲哚、吲唑、噁唑并[4,5-b]吡啶、噁唑并[5,4-b]吡啶。
  3. 根据权利要求2所述的化合物，其特征在于，芳杂环选自下述基团：
    Figure PCTCN2022120795-appb-100003
  4. 根据权利要求1所述的化合物，其特征在于，R 1表示H、芳环或芳杂环，其中芳环或芳杂环为无取代、单取代或多取代，芳环或芳杂环选自苯基、呋喃基、噻吩基、吡咯基、噁唑基、异噁唑基、咪唑基、吡唑基、噻唑基、异噻唑基、三氮唑基、1,3,4-噁二唑基、1,3,4-噻二唑基、1,2,4-噁二唑基、1,2,4-噻二唑基、吡啶基、嘧啶基、哒嗪基，氧茚基、吲哚基、喹啉基、异喹啉基、吲唑基、苯并噁唑基、苯并噻唑基、嘌呤基、噁唑并吡啶基；芳环或芳 杂环上的取代基选自H、F、Cl、Br、I、CF 3、CN、羟基、甲氧基、甲基、硝基、巯基、羧基、乙烯基、溴甲基、氰甲基、C1-C10直链或支链烷烃氧基、C1-C10直链卤代烷烃或卤代支链烷烃基、卤代环烷烃，C1-C10直链烷烃或支链烷烃、环烷烃，C1-C10直链或支链烷烃取代巯基、C1-C10直链或支链烷烃酰胺基、C1-C10直链或支链烷烃酯基。
  5. 根据权利要求4所述的化合物，其特征在于，R 1中，芳环选自
    Figure PCTCN2022120795-appb-100004
    芳环上的取代基选自H、F、Cl、Br、I、甲氧基、甲基。
  6. 根据权利要求1所述的化合物，其特征在于，
    L选自-CO-或-CH 2-；
    和/或，A为5-6元饱和或不饱和的含有1-2个杂原子N或O的杂环；
    和/或，R 2选自H、甲基、乙基、乙酰基、苯基、吡啶基、甲氧酰基、丙酰基、甲氧乙酰基、乙氧乙酰基；优选为H、甲基；
    和/或，R 3选自H、F、Cl、Br、I、CF 3、CN、羟基、甲氧基、甲基、硝基、巯基、羧基、乙烯基、溴甲基、氰甲基、芳基、杂环基，C1-C10直链烷烃或支链烷烃、环烷烃，C1-C10直链或支链烷烃氧基，C1-C10直链或支链烷烃取代巯基、C1-C10直链或支链烷烃酯基；优选为H、F、Cl、Br、I。
  7. 根据权利要求1所述的化合物，其特征在于，其中
    Figure PCTCN2022120795-appb-100005
    选自下述基团：
    Figure PCTCN2022120795-appb-100006
    Figure PCTCN2022120795-appb-100007
  8. 根据权利要求1所述的化合物，其特征在于，式I所示的化合物选自：
    Figure PCTCN2022120795-appb-100008
    Figure PCTCN2022120795-appb-100009
    Figure PCTCN2022120795-appb-100010
  9. 权利要求1-8任一项所述的式I所示的化合物或其药学上可接受的盐在制备预防和/或治疗与FAAH相关疾病的药物中的应用。
  10. 根据权利要求9所述的应用，其特征在于，所述与FAAH相关疾病包括炎症性疾病、类风湿性关节炎、肝炎、肝纤维化、自身免疫病、疼痛、抑郁、疼痛抑郁共病、自闭症、社交恐惧症、图雷特氏综合症、神经退行性疾病、焦虑创伤后应激、大麻素使用紊乱疾病、药物戒断、肿瘤。
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