A substituted heterocyclic compound containing an alpha-ketone skeleton and its use

Abstract

The invention discloses a substituted heterocyclic compound containing an α-ketone skeleton and a use thereof, and relates to the field of pharmaceutical chemistry, and specifically relates to a substituted heterocyclic compound containing an α-ketone skeleton or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing these compounds and their medical uses, in particular, an application of the substituted heterocyclic compound as a fatty amide hydrolase (FAAH) inhibitor in the preparation of a drug for preventing or treating diseases related to FAAH, including inflammatory diseases, rheumatoid arthritis, hepatitis, liver fibrosis, autoimmune diseases, pain, depression, pain-depression comorbidity, autism, social phobia, Tourette syndrome, neurodegenerative diseases, anxiety post-traumatic stress (PTSD), cannabinoid use disorder, drug withdrawal, and anti-tumor treatment.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and relates to a substituted heterocyclic compound containing an α-ketone skeleton, and specifically relates to a substituted heterocyclic FAAH inhibitor containing an α-ketone skeleton, and application of the inhibitor in the preparation of a drug for preventing and / or treating diseases related to FAAH. Background Art

[0002] Chronic pain is not an early warning to prevent physical injury or disease, but the result of abnormal neural mechanisms, which usually persists or recurs for more than 3 to 6 months. There is increasing evidence that chronic pain is a multifactorial disease that exacerbates underlying mood disorders such as anxiety and depression, thereby complicating drug treatment. The high prevalence and long duration of chronic pain not only significantly reduce an individual's health status and quality of life, but also impose a huge economic burden on society as a whole.

[0003] At present, 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; when opioid treatment is ineffective, antidepressants such as tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitors, anti-epileptic drugs such as gabapentin and pregabalin show special analgesic effects. However, long-term use of non-steroidal anti-inflammatory drugs can cause serious gastrointestinal and renal side effects, and may also increase cardiovascular risks; the use of opioids can cause side effects such as respiratory depression, addiction, nausea, confusion and immunosuppression, and is not suitable for long-term drug treatment of chronic pain. Therefore, the development of new analgesics has important research value and scientific significance.

[0004] 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 various diseases such as pain, anxiety, depression, and cardiovascular diseases. It is mainly composed of endogenous cannabinoids N-arachidonic acid ethanolamine (AEA), N-arachidonic acid glycerol (2-AG), cannabinoid receptors (CB1, CB2), and enzymes related to the synthesis and degradation of endogenous cannabinoids. AEA is the most widely studied endogenous cannabinoid receptor (CB1, CB2) agonist, which can be decomposed into ethanolamine and AA by fatty amide hydrolase (FAAH) in the body and inactivated.

[0005] Studies have shown that the protective effects of the endocannabinoid system (ECS) are achieved through the activation of CB receptors. Many preclinical studies have confirmed that gene knockout or drug inhibitors to inactivate FAAH can increase the body's endogenous AEA content, thereby activating receptors such as CB and TRPV1, and exerting multiple physiological effects such as anti-inflammatory, analgesic, anti-depressant, regulation of cannabinoid disorders, and drug withdrawal. ECS is upregulated in many pathological and physiological conditions, such as inflammation, neurodegenerative diseases, gastrointestinal reactions, metabolic and cardiovascular diseases, pain, and cancer, and plays a self-protective role in inhibiting disease progression or reducing signs and symptoms. Therefore, inhibiting the degradation of endogenous cannabinoids is a therapeutic approach for treating a variety of diseases.

[0006] In vivo, endogenous cannabinoids are released outside the cells and are rapidly cleared through cell absorption or hydrolysis. Fatty acid amide hydrolase (FAAH) is the main metabolic hydrolase of AEA. FAAH enzyme is the main enzyme regulating the metabolism of endogenous lipid molecules fatty amides. Inhibition of FAAH can increase the level of endogenous fatty amides. Studies have shown that FAAH inhibitors can exert antidepressant effects through multiple pathways such as anti-inflammation, neuroprotection, and improvement of HPA axis disorders; at the same time, FAAH inhibitors can also inhibit adenylate cyclase and regulate Na by activating G proteins. + / K + Ion channels play an analgesic role. It is also found that the endocannabinoid system plays an analgesic role in chronic pain mainly by inhibiting glial cell activation and central sensitization.

[0007] By inhibiting the activity of FAAH, the metabolism of AEA can be reduced, thereby activating CB receptors and exerting analgesic effects. In recent years, indirect activation of CB receptors by inhibiting FAAH has become a research hotspot for analgesics. Some FAAH inhibitors have entered clinical research, providing a new way to develop new, safe and effective analgesics and other related disease treatment drugs. Summary of the invention

[0008] Objective: The present invention provides a substituted heterocyclic compound containing an α-keto skeleton and having FAAH inhibitory activity and uses thereof.

[0009] Technical solution: To solve the above technical problems, the technical solution adopted by the present invention is:

[0010] In the first aspect of the present invention, a substituted heterocyclic compound containing an α-keto skeleton is provided, which is a compound shown in Formula I or a pharmaceutically acceptable salt thereof:

[0011]

[0012] in,

[0013] Ar is an unsubstituted, monosubstituted or polysubstituted aromatic heterocycle;

[0014] R1 represents H or an aromatic ring or an aromatic heterocyclic ring;

[0015] L represents a connecting chain selected from -O-, -S-, -NR4-, or -(CH2) n -, n = 0, 1, 2, 3; R4 is selected from H, C1-C8 straight chain halogenated alkane or halogenated branched alkane, halogenated cycloalkane, C1-C8 straight chain alkane or branched alkane, cycloalkane;

[0016] A is a 4-7 membered saturated or unsaturated heterocyclic ring containing 1-2 heteroatoms N, S or O;

[0017] R2 and R3 each independently represent H or a substituent.

[0018] (1) Ar is an unsubstituted, monosubstituted or polysubstituted aromatic heterocycle, wherein the aromatic heterocycle is selected from the group consisting of 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, benzoxazole, benzothiazole, purine, quinoline, isoquinoline, indole, indazole, oxazolo[4,5-b]pyridine, and oxazolo[5,4-b]pyridine.

[0019] In some embodiments, the aromatic heterocycle is selected from the following groups:

[0020]

[0021] (2) R1 represents H, an aromatic ring or an aromatic heterocyclic ring, wherein the aromatic ring or aromatic heterocyclic ring is unsubstituted, monosubstituted or polysubstituted, and the aromatic ring or aromatic heterocyclic ring is selected from phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolinyl, indolyl, quinolyl, isoquinolyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, Oxazolopyridinyl; the substituents on the aromatic ring or aromatic heterocyclic ring are selected from H, F, Cl, Br, I, CF3, CN, hydroxyl, methoxy, methyl, nitro, mercapto, carboxyl, vinyl, bromomethyl, cyanomethyl, C1-C10 straight chain or branched alkaneoxy, C1-C10 straight chain halogenated alkane or halogenated branched alkane, halogenated cycloalkane, C1-C10 straight chain alkane or branched alkane, cycloalkane, C1-C10 straight chain or branched alkane substituted mercapto, C1-C10 straight chain or branched alkane amide, C1-C10 straight chain or branched alkane ester.

[0022] In some embodiments, in R1, the aromatic ring is selected from

[0023] The substituents on the aromatic ring are selected from H, F, Cl, Br, I, methoxy, and methyl.

[0024] In some embodiments, L is selected from -CO- or -CH2-;

[0025] and / or, A is a 5-6 membered saturated or unsaturated heterocyclic ring containing 1-2 heteroatoms N or O;

[0026] and / or, R2 is selected from H, methyl, ethyl, acetyl, phenyl, pyridyl, methoxyacyl, propionyl, methoxyacetyl, ethoxyacetyl; preferably H, methyl;

[0027] And / or, R3 is selected from H, F, Cl, Br, I, CF3, CN, hydroxyl, methoxy, methyl, nitro, thiol, carboxyl, vinyl, bromomethyl, cyanomethyl, aryl, heterocyclic group, C1-C10 straight-chain alkane or branched alkane, cycloalkane, C1-C10 straight-chain or branched alkaneoxy, C1-C10 straight-chain or branched alkane substituted thiol, C1-C10 straight-chain or branched alkane ester group; preferably H, F, Cl, Br, I.

[0028] In some embodiments, Selected from the following groups:

[0029]

[0030] Further, the compound represented by formula I is selected from:

[0031]

[0032]

[0033]

[0034] The second aspect of the present invention provides a method for preparing the compound shown in formula I.

[0035]

[0036] When R1 is H, Ar is furanyl, thienyl, pyridyl, or a fused heterocycle such as oxazoline, the first preparation method is used to construct Intermediate 1:

[0037]

[0038] When R1 is H, Ar is a single heterocycle containing two heteroatoms such as oxazole, thiazole, or a fused heterocycle such as benzoxazole, benzothiazole, the second preparation method is used to construct Intermediate 1:

[0039]

[0040] When R1 is an unsubstituted, monosubstituted or polysubstituted aromatic ring, and Ar is a furanyl group, a 1,3,4-oxadiazole group, etc., the third preparation method is used to construct Intermediate 1:

[0041]

[0042] On the other hand, a pharmaceutical composition contains a therapeutically effective amount of one or more of the compounds or their pharmaceutically acceptable salts or stereoisomers or prodrugs and a pharmaceutically acceptable carrier; the pharmaceutically acceptable carrier is a filler, a lubricant, an emulsifier, a wetting agent, a colorant, a flavoring agent, a stabilizer, an antioxidant, and a preservative.

[0043] The third aspect of the present invention is the use of the compound and the pharmaceutical composition as FAAH inhibitors in the preparation of drugs for preventing and / or treating diseases related to FAAH.

[0044] Furthermore, the FAAH-related diseases include inflammatory diseases, rheumatoid arthritis, hepatitis, liver fibrosis, autoimmune diseases, pain, depression, pain-depression comorbidity, autism, social phobia, Tourette syndrome, neurodegenerative diseases, anxiety and post-traumatic stress (PTSD), cannabinoid use disorders, drug withdrawal, and anti-tumor treatment.

[0045] The present invention has confirmed through a large number of modern pharmacological scientific studies that substituted heterocyclic compounds containing an α-keto skeleton have good inhibitory activity on FAAH and are suitable for diseases related to FAAH. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 For the anti-inflammatory activity test of the compound (*p<0.01vs control group, #p<0.05vs LPSgroup, ##p<0.01vs LPS group);

[0047] Figure 2 This is a sugar water preference experiment study (*p<0.01vs control group, #p<0.01vs Model group);

[0048] Figure 3 This is an open field experiment study (*, P value compared to control group (*P<0.01); # ,Pvalue compared to model group(# P<0.05, ## P<0.01).). DETAILED DESCRIPTION

[0049] In order to further illustrate the present invention, a series of examples are given below. These examples are purely illustrative and are only used to specifically describe the present invention, and should not be understood as limiting the present invention.

[0050] Example 1: Preparation of compounds

[0051] 5-Chloro-1-methyl-1H-indole-2-carboxylic acid ethyl ester

[0052] Dissolve 5-chloro-2-indolecarboxylic acid ethyl ester (1g, 4.47mmol, 1eq) in N,N-dimethylformamide, add sodium hydride (215mg, 8.94mmol, 2eq), stir at 80°C for 1 hour under nitrogen protection, add iodomethane (834μl, 13.41mmol, 3eq), and monitor the reaction progress by TLC. After the reaction is completed, add saturated ammonium chloride to quench, extract with dichloromethane (3×30mL), dry the organic phase with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and separate and purify by column chromatography to obtain 817mg of light yellow solid with a yield of 77%. 1 HNMR(400MHz,DMSO-d6)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.

[0053] 5-Chloro-1-methyl-1H-indole-2-carboxylic acid

[0054] 5-Chloro-1-methyl-1H-indole-2-carboxylic acid ethyl ester (817 mg, 3.45 mmol, 1 eq) was dissolved in aqueous methanol solution, sodium hydroxide (552 mg, 13.8 mmol, 4 eq) was added, and the mixture was stirred at 60°C for 2 hours. 1 mol / L hydrochloric acid was added to adjust the pH to 2. A large amount of solid precipitated, which was filtered and dried to obtain 646 mg of a white solid with a yield of 90%. 1 H NMR (400MHz, DMSO-d6) 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.

[0055] 1-Methyl-1H-indole-2-carboxylic acid ethyl ester

[0056] The same synthetic method as 6-chloro-1-methyl-1H-indole-2-carboxylic acid ethyl ester was used, and indole-2-carboxylic acid ethyl ester was used as the raw material to obtain 235 mg of a light yellow solid with a yield of 44%. 1 H NMR (400MHz, CDCl3) 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.

[0057] 1-Methyl-1H-indole-2-carboxylic acid

[0058] 1-Methyl-1H-indole-2-carboxylic acid ethyl ester (280 mg, 1.38 mmol, 1 eq) was dissolved in methanol aqueous solution, sodium hydroxide (221 mg, 5.52 mmol, 4 eq) was added, and the mixture was stirred at 60°C for 2 hours, and the reaction progress was monitored by TLC. After the reaction was completed, 1 mol / L hydrochloric acid was added to adjust the pH to 2, and only a small amount of solid was precipitated, so it was extracted three times with dichloromethane: methanol = 10:1, and the combined organic phase was added with anhydrous sodium sulfate and dried for 30 minutes, and filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain 203 mg of off-white solid, with a yield of 84%. 1 HNMR(400MHz, DMSO-d6)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.

[0059] tert-Butyl 4-(2-toluenesulfonylbenzylidene)piperidine-1-carboxylate

[0060] N-Boc-piperidone (1 g, 5 mmol, 1 eq) and p-toluenesulfonyl hydrazide (935 mg, 5 mmol, 1 eq) were dissolved in methanol and reacted at room temperature for 6 h. After the reaction, the mixture was concentrated under reduced pressure to obtain 1.56 g of a white solid with a yield of 84%. 1 H 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).

[0061] 4-Nicotinylpiperidine-1-carboxylic acid tert-butyl ester

[0062] Dissolve tert-butyl 4-(2-toluenesulfonylbenzylidene)piperidine-1-carboxylate (500 mg, 1.36 mmol, 1 eq) and 3-pyridinecarboxaldehyde (127 μl, 1.36 mmol, 1 eq) in anhydrous 1,4-dioxane, add cesium carbonate (220 mg, 2.04 mmol, 1.5 eq), heat to 110°C and stir for 3 hours, quench with saturated ammonium chloride solution, extract with dichloromethane (3×35 mL), add anhydrous sodium sulfate to the combined organic phases, dry, evaporate the solvent under reduced pressure, and separate and purify by column chromatography to obtain 190 mg of a light yellow oil with a yield of 48%. 1 H NMR (300MHz, DMSO-d6) 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=7.9,4.8,0.9H z,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.

[0063] tert-Butyl 4-isonicotinamidopiperidine-1-carboxylate

[0064] Dissolve tert-butyl 4-(2-toluenesulfonylbenzylidene)piperidine-1-carboxylate (500 mg, 1.36 mmol, 1 eq) and 3-pyridinecarboxaldehyde (127 μl, 1.36 mmol, 1 eq) in anhydrous 1,4-dioxane, add cesium carbonate (220 mg, 2.04 mmol, 1.5 eq), heat to 110°C and stir for 3 hours, quench with saturated ammonium chloride solution, extract with dichloromethane (3×35 mL), add anhydrous sodium sulfate to the combined organic phases, dry, evaporate the solvent under reduced pressure, and separate and purify by column chromatography to obtain 388 mg of a light yellow oil in a yield of 98%. 1 H NMR (400MHz, DMSO-d6) 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.

[0065] Piperidin-4-yl(pyridin-4-yl)methanone

[0066] Dissolve tert-butyl 4-isonicotinamidopiperidine-1-carboxylate in HCl / EA, stir at room temperature for half an hour, filter and dry to obtain 230 mg of a light yellow solid with a yield of 82%. 1 H NMR (400MHz, DMSO-d6) 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.

[0067] (5-Chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone (I-1)

[0068]

[0069] Piperidin-4-yl(pyridin-4-yl)methanone (200 mg, 0.885 mmol, 1.0 eq) and 5-chloro-1-methyl-1H-indole-2-carboxylic acid (185 mg, 0.885 mmol, 1.0 eq) were dissolved in N,N-dimethylformamide, and EDCI (85 mg, 0.442 mmol, 0.5 eq), 1-hydroxybenzotriazole (60 mg, 0.442 mmol, 0.5 eq) and N-methylmorpholine (195 μl, 1.77 mmol, 1.0 eq) were added. After stirring at room temperature for 0.5 hour, 30 mL of water was added, and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic phases were added with anhydrous sodium sulfate and dried, and the solvent was evaporated under reduced pressure. The mixture was separated and purified by column chromatography to obtain 112 mg of a white solid with a yield of 33%. 1 HNMR (400MHz, DMSO-d6) 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] + Calculate for C 21 H 21 ClN3O2,382.1317; found 382.1370.

[0070] (4-isonicotinamidopiperidin-1-yl)(1-methyl-1H-indol-2-yl)methanone (I-2)

[0071]

[0072] The same synthetic method as (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone was used, with piperidin-4-yl(pyridin-4-yl)methanone and 1-methyl-1H-indole-2-carboxylic acid as raw materials to obtain 208 mg of beige solid with a yield of 68%. 1 H NMR (400MHz, DMSO-d6) 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; 13 C NMR (101MHz, CDCl3) δ200.95,162.73,151.19,141.63,136.28,132.86,127.28,12 5.97,123.75,121.19,120.75,110.95,102.70,43.62,31.32,28.37ppm; HRMS(ESI + ):m / z[M+H] + Calculate for C 21 H 21 N3O2,348.1707; found 348.1757.

[0073] tert-Butyl 4-picolinate-1-carboxylate

[0074] The same synthesis method as tert-butyl 4-isonicotinamidopiperidine-1-carboxylate was used, with tert-butyl 4-(2-toluenesulfonylbenzylidene)piperidine-1-carboxylate and 2-pyridinecarboxaldehyde as raw materials to obtain 249 mg of a light yellow oil with a yield of 63%. 1 H NMR (300MHz, DMSO-d6) 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).

[0075] Piperidin-4-yl(pyridin-2-yl)methanone

[0076] Dissolve tert-butyl 4-picolinate-1-carboxylate in HCl / EA, stir at room temperature for half an hour, filter and dry to obtain 172 mg of a light yellow solid with a yield of 88%. 1 H NMR (400MHz, DMSO-d6) 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),3.2 9(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.

[0077] (5-Chloro-1-methyl-1H-indol-2-yl)(4-pyridinylpiperidin-1-yl)methanone (I-3)

[0078]

[0079] The same synthetic method as (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone was used as piperidin-4-yl(pyridin-2-yl)methanone and 5-chloro-1-methyl-1H-indole-2-carboxylic acid to obtain 53 mg of a light yellow solid with a yield of 29%. 1 H NMR(400MHz, DMSO-d6)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] + Calculate for C 21 H 21 ClN3O2,382.1317; found 382.1365.

[0080] (1-(Benzofuran-2-carbonyl)piperidin-4-yl)(pyridin-2-yl)methanone (I-4)

[0081]

[0082] The same synthesis method as (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinoylpiperidin-1-yl)methanone was used, with benzofuran-2-carboxylic acid and piperidin-4-yl(pyridin-2-yl)methanone as raw materials to obtain 137 mg of a white solid with a yield of 46.44%. 1 H 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).

[0083] (4-Pyridinylpiperidinyl)(quinolin-3-yl)methanone (I-5)

[0084]

[0085] The same synthesis method as (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone was used, with quinoline-3-carboxylic acid and piperidin-4-yl(pyridin-2-yl)methanone as raw materials to obtain 159 mg of a white solid with a yield of 52.18%. 1HNMR(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).

[0086] Pyridin-2-yl(1-(quinolin-3-ylmethyl)piperidin-4-yl)methanone (I-6)

[0087]

[0088] Piperidin-4-yl(pyridin-2-yl)methanone (200 mg, 1.05 mmol, 1 eq) was dissolved in acetonitrile, potassium carbonate (647 mg, 4.21 mmol, 4 eq) and potassium iodide (388 mg, 2.10 mmol, 2 eq) were added, and 3-(bromomethyl)quinoline (218 mg, 1.58 mmol, 1.5 eq) was added after stirring at room temperature for 30 minutes. The mixture was heated to 80°C and stirred for 2.5 hours, then filtered off with suction, and the filtrate was extracted with dichloromethane (3×30 mL) after adding water. The combined organic phase was washed with 10% potassium dihydrogen phosphate (3×30 mL) and then with saturated brine (3×30 mL), and finally dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was separated and purified by column chromatography to obtain 109 mg of a light yellow solid with a yield of 31%. 1 H 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).

[0089] tert-Butyl 4-(oxazole-2-carbonyl)piperidine-1-carboxylate

[0090] Oxazole (284 μl, 4.32 mmol, 1.2 eq) was dissolved in anhydrous THF, and LDA (3.6 ml, 7.2 mmol, 2 eq) was slowly added at -40°C. After stirring for 30 min, a THF solution of 1-Boc-4-[(methyloxy)methylcarbamoyl]piperidine (1 g, 3.6 mmol, 1 eq) was added, and then the temperature was raised to room temperature to react overnight. After the reaction was completed, saturated ammonium chloride solution was added to quench, and then EA was used for extraction 3 times, the organic phases were combined, and then washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain 228 mg, with a yield of 22%. 1 H NMR (400MHz, CDCl3) 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.

[0091] Oxazol-2-yl(piperidin-4-yl)methanone

[0092] Dissolve tert-butyl 4-(oxazole-2-carbonyl)piperidine-1-carboxylate in a small amount of EA, add HCl / EA, and react at room temperature for 30 minutes. A large amount of white solid precipitates, which is filtered and dried to obtain 134 mg of white solid. The yield is 87%. 1 H NMR (400MHz, DMSO-d6) 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.

[0093] (5-Chloro-1-methyl-1H-indol-2-yl)(4-(oxazole-2-carbonyl)piperidin-1-yl)methanone (I-7)

[0094]

[0095] Referring to the synthesis method of (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone, 79 mg of solid was obtained with a yield of 23%. 1H NMR (400MHz, DMSO-d6) 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] + Calculate for C 19 H 19 ClN3O3,372.1109; found 372.1164.

[0096] tert-Butyl 4-(thiazole-2-carbonyl)piperidine-1-carboxylate

[0097] Thiazole (312 μl, 4.41 mmol, 1.2 eq) was dissolved in anhydrous THF, and LDA (3.6 ml, 7.2 mmol, 2 eq) was slowly added at -40 °C. After stirring for 30 min, a THF solution of 1-Boc-4-[(methyloxy)methylcarbamoyl]piperidine (1 g, 3.67 mmol, 1 eq) was added, and then the mixture was heated to room temperature and reacted overnight. After the reaction was completed, saturated ammonium chloride solution was added to quench, and then EA was used for extraction 3 times, the organic phases were combined, and then washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain 228 mg, with a yield of 22%. , 595 mg of light yellow oil was obtained, with a yield of 56%. 1 H NMR(400MHz, CDCl3) 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).

[0098] Piperidin-4-yl(thiazol-2-yl)methanone

[0099] Dissolve tert-butyl 4-(thiazole-2-carbonyl)piperidine-1-carboxylate in a small amount of EA, add HCl / EA, and react at room temperature for 30 minutes. A large amount of white solid precipitates, which is filtered and dried to obtain 376 mg of white solid. The yield is 87%. 1H NMR (400MHz, DMSO-d6) 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.

[0100] (5-Chloro-1-methyl-1H-indol-2-yl)(4-(thiazole-2-carbonyl)piperidin-1-yl)methanone (I-8)

[0101]

[0102] Referring to the synthesis method of (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone, 237 mg of solid was obtained with a yield of 47%. 1 H 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),6.6 5(d,J=3.0Hz,1H),4.71–4.35(m,1H),4.21–3.96(m,1H),3.95–3.83(m,1 H),3.76(s,3H),3.31–3.00(m,2H),2.16–1.90(m,2H),1.78–1.54(m,2H).

[0103] tert-Butyl 4-(Benzo[d]thiazole-2-carbonyl)piperidine-1-carboxylate

[0104] The same synthesis method as tert-butyl 4-(thiazole-2-carbonyl)piperidine-1-carboxylate was used, with benzothiazole as the raw material to obtain 325 mg of a light yellow solid with a yield of 51%. 1 H NMR (300MHz, DMSO-d6) 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.

[0105] Benzo[d]thiazol-2-yl(piperidin-4-yl)methanone

[0106] Dissolve benzo[d]thiazol-2-yl(piperidin-4-yl)methanone in a small amount of EA, add HCl / EA, and react at room temperature for 30 minutes. A large amount of white solid precipitates, which is filtered and dried to obtain 256 mg of white solid, with a yield of 97%. 1 H NMR (300MHz, DMSO-d6) 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.

[0107] Benzo[d]thiazol-2-yl(1-(5-chloro-1-methyl-1H-indole-2-carbonyl)piperidin-4-yl)methanone (I-9)

[0108]

[0109] Referring to the synthesis method of (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone, 24 mg of solid was obtained with a yield of 30%. 1 H NMR(300MHz,DMSO-d6)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] + Calculate for C 23 H 21 ClN3O2S,438.1038; found 438.1118.

[0110] 5-Benzoxazole

[0111] Benzaldehyde (1 g, 9.42 mmol, 1 eq) was dissolved in methanol, and p-methylbenzenesulfonyl isocyanide (2.023 g, 10.362 mmol, 1.1 eq) and K2CO3 (2.598 g, 18.8 mmol, 2 eq) were added, and the mixture was refluxed at 80°C for 1.5 h. After the reaction was completed, the methanol was removed by concentration under reduced pressure, and the insoluble K2CO3 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 solid, with a yield of 74%. 1H NMR (300MHz, DMSO-d6) 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.

[0112] tert-Butyl 4-(5-phenyloxazole-2-carbonyl)piperidine-1-carboxylate

[0113] 5-Benzoxazole (320 mg, 2.208 mmol, 1.2 eq) was dissolved in anhydrous THF, and LDA (1.1 ml, 2.208 mmol, 1.2 eq) was slowly added at -40 °C, and a THF solution of 1-Boc-4-[(methyloxy)methylcarbamoyl]piperidine (500 mg, 1.84 mmol, 1 eq) was added after stirring for 30 min, and then the mixture was heated to room temperature and reacted overnight. After the reaction was completed, saturated ammonium chloride solution was added to quench, and then EA was used for extraction 3 times, the organic phases were combined, and then washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain 325 mg of a solid with a yield of 37%. 1 H 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,2 H),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).

[0114] (5-phenyloxazol-2-yl)(piperidin-4-yl)methanone

[0115] Dissolve tert-butyl 4-(5-phenyloxazole-2-carbonyl)piperidine-1-carboxylate in hydrogen chloride-dioxane solution and react at room temperature for 30 minutes. A large amount of white solid precipitates. Filter and dry to obtain 152 mg of solid with a yield of 77%. 1 H 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).

[0116] (5-Chloro-1-methyl-1H-indol-2-yl)(4-(5-phenyloxazole-2-carbonyl)piperidin-1-yl)methanone (I-10)

[0117]

[0118] Referring to the synthesis method of (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone, 18 mg of solid was obtained with a yield of 24%. 1 H 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),7.31–7.1 9(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).

[0119] 2-Phenyl-1,3,4-oxadiazole

[0120] Benzoyl hydrazide (1 g, 7.345 mmol, 1 eq) was dissolved in trimethyl orthoformate, p-toluenesulfonic acid (126 mg, 0.7345 mmol, 0.1 eq) was added, and the mixture was refluxed at 120° C. for 1.5 h. After the reaction was completed, the solid was directly purified by column chromatography to obtain 1.05 g of solid with a yield of 98%. 1 H NMR (400MHz, DMSO-d6) δ9.36(s,1H),7.91–7.86(m,2H),7.68–7.53(m,3H).

[0121] tert-Butyl 4-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)piperidine-1-carboxylate

[0122] 2-phenyl-1,3,4-oxadiazole (323 mg, 2.21 mmol, 1.2 eq) was dissolved in anhydrous THF, and n-BuLi (0.88 ml, 2.21 mmol, 1.2 eq) was slowly added at -40 °C, and a THF solution of 1-Boc-4-[(methyloxy)methylcarbamoyl]piperidine (500 mg, 1.84 mmol, 1 eq) was added after stirring for 30 min, and then the mixture was heated to room temperature to react overnight. After the reaction was completed, saturated ammonium chloride solution was added to quench, and then EA was used for extraction 3 times, the organic phases were combined, and then washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain 227 mg of solid with a yield of 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).

[0123] (5-phenyl-1,3,4-oxadiazol-2-yl)(piperidin-4-yl)methanone

[0124] 227 mg of tert-butyl 4-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)piperidine-1-carboxylate was dissolved in hydrogen chloride-dioxane solution and reacted at room temperature for 30 min. A large amount of white solid precipitated, which was filtered and dried to obtain 120 mg of solid with a yield of 65%. 1 HNMR(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).

[0125] (5-Chloro-1-methyl-1H-indol-2-yl)(4-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)piperidin-1-yl)methanone (I-11)

[0126]

[0127] Referring to the synthesis method of (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone, 16 mg of solid was obtained with a yield of 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).

[0128] 2-(Pyridin-3-yl)-1,3,4-oxadiazole

[0129] 3-Pyridinecarboxylic acid hydrazide (1 g, 7.3 mmol, 1 eq) was dissolved in trimethyl orthoformate, p-toluenesulfonic acid (126 mg, 0.73 mmol, 0.1 eq) was added, and the mixture was refluxed at 120°C for 1.5 h. After the reaction, EA was added for dilution, and the mixture was washed with water and saturated brine for 3 times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 915 mg of a white solid with a yield of 85%. 1 H NMR (300MHz, DMSO-d6) δ9.47 (d, J = 3.0 Hz, 1H), 9.22 (d, J = 2.9 Hz, 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.

[0130] tert-Butyl 4-(hydroxy(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)piperidine-1-carboxylate

[0131] 2-(Pyridin-3-yl)-1,3,4-oxadiazole (250 mg, 1.7 mmol, 1 eq) was dissolved in anhydrous THF, and LDA (1.3 ml, 2.55 mmol, 1.5 eq) was slowly added at -78 °C, and a THF solution of 1-Boc-4-piperidinecarboxaldehyde (362 mg, 1.7 mmol, 1 eq) was added after stirring for 30 min, and then the mixture was warmed to room temperature and the reaction was continued for 3 h. After the reaction was completed, a saturated ammonium chloride solution was added to quench the mixture, and then EA was used for extraction 3 times, the organic phases were combined, and then washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain 290 mg of a light yellow solid with a yield of 47%. 1H NMR (300MHz, DMSO-d6) 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=5.6 Hz,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.

[0132] tert-Butyl 4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-carbonyl)piperidine-1-carboxylate

[0133] Dess-Martin periodinane (636 mg, 1.5 mmol, 2 eq) was added to a solution of tert-butyl 4-(hydroxy(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)piperidine-1-carboxylate (270 mg, 0.75 mmol, 1 eq) in DCM, and the mixture was reacted at room temperature for 30 min. After the reaction, a saturated sodium bicarbonate solution was added and stirred for 5 min, followed by extraction with EA for 3 times, the organic phases were combined, and then washed with saturated sodium bicarbonate and saturated brine for 3 times, respectively, and dried over anhydrous sodium sulfate. Finally, 182 mg of a light yellow solid was obtained by column chromatography, with a yield of 68%. 1 H NMR (300MHz, DMSO-d6) 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.

[0134] Piperidin-4-yl(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methanone

[0135] 182 mg of tert-butyl 4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-carbonyl)piperidine-1-carboxylate was dissolved in hydrogen chloride-dioxane solution and reacted at room temperature for 30 min. A large amount of white solid precipitated, which was filtered and dried to obtain 111 mg of white solid with a yield of 84%. 1H NMR (300MHz, DMSO-d6) 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.

[0136] (5-Chloro-1-methyl-1H-indol-2-yl)(4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-carbonyl)piperidin-1-yl)methanone (I-12)

[0137]

[0138] Referring to the synthesis method of (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone, 18 mg of a white solid was obtained with a yield of 11.7%. 1 H 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).

[0139] 2-(3-Chlorophenyl)-1,3,4-oxadiazole

[0140] 3-Chlorobenzoylhydrazide (1 g, 7.3 mmol, 1 eq) was dissolved in trimethyl orthoformate, p-toluenesulfonic acid (126 mg, 0.73 mmol, 0.1 eq) was added, and the mixture was refluxed at 120°C for 1.5 h. After the reaction was completed, EA was added for dilution, and the mixture was washed with water and saturated brine for 3 times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 915 mg of a white solid with a yield of 85%. 1H NMR (300MHz, DMSO-d6) δ9.47 (d, J = 3.0 Hz, 1H), 9.22 (d, J = 2.9 Hz, 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.

[0141] tert-Butyl 4-((5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl)(hydroxy)methyl)piperidine-1-carboxylate

[0142] 2-(3-chlorophenyl)-1,3,4-oxadiazole (250 mg, 1.7 mmol, 1 eq) was dissolved in anhydrous THF, and LDA (1.3 ml, 2.55 mmol, 1.5 eq) was slowly added at -78 °C, and a THF solution of 1-Boc-4-piperidinecarboxaldehyde (362 mg, 1.7 mmol, 1 eq) was added after stirring for 30 min, and then the mixture was warmed to room temperature and the reaction was continued for 3 h. After the reaction was completed, a saturated ammonium chloride solution was added to quench the mixture, and then EA was used for extraction 3 times, the organic phases were combined, and then washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain 290 mg of a light yellow solid with a yield of 47%. 1 H NMR (300MHz, DMSO-d6) 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=5.6 Hz,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.

[0143] tert-Butyl 4-(5-(3-chlorophenyl)-1,3,4-oxadiazole-2-carbonyl)piperidine-1-carboxylate

[0144] Dess-Martin periodinane (636 mg, 1.5 mmol, 2 eq) was added to a solution of tert-butyl 4-((5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (270 mg, 0.75 mmol, 1 eq) in DCM, and the mixture was reacted at room temperature for 30 min. After the reaction, a saturated sodium bicarbonate solution was added and stirred for 5 min, followed by extraction with EA 3 times, the organic phases were combined, and then washed with saturated sodium bicarbonate and saturated brine 3 times, respectively, and dried over anhydrous sodium sulfate. Finally, 182 mg of a light yellow solid was obtained by column chromatography purification with a yield of 68%. 1 H NMR (300MHz, DMSO-d6) 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.

[0145] (5-(3-Chlorophenyl)-1,3,4-oxadiazol-2-yl)(piperidin-4-yl)methanone

[0146] 182 mg of tert-butyl 4-(5-(3-chlorophenyl)-1,3,4-oxadiazole-2-carbonyl)piperidine-1-carboxylate was dissolved in hydrogen chloride-dioxane solution and reacted at room temperature for 30 min. A large amount of white solid precipitated, which was filtered and dried to obtain 111 mg of white solid with a yield of 84%. 1 H NMR (300MHz, DMSO-d6) 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.

[0147] (5-Chloro-1-methyl-1H-indol-2-yl)(4-(5-(3-chlorophenyl)-1,3,4-oxadiazole-2-carbonyl)piperidin-1-yl)methanone (I-13)

[0148]

[0149] Referring to the synthesis method of (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone, 18 mg of a white solid was obtained with a yield of 11.7%. 1 H 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).

[0150] 6-Chloropyridine-2-carboxylic acid hydrazide

[0151] Dissolve methyl 6-chloro-2-pyridinecarboxylate (2 g, 11.66 mmol, 1 eq) in methanol, add hydrazine hydrate (0.7 g, 14 mmol, 1.2 eq), stir at room temperature for 20 min, remove the solvent methanol by distillation under reduced pressure, add MTBE and stir for 15 min, filter to obtain a white powdery solid, dry in a vacuum oven, weigh 1.32 g of a white powdery solid, and the yield is 66%. 1 H 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).

[0152] 2-(3-Chloropyridin-2-yl)-1,3,4-oxadiazole

[0153] 6-Chloropyridine-2-carboxylic acid hydrazide (1 g, 5.83 mmol, 1 eq) was dissolved in trimethyl orthoformate, p-toluenesulfonic acid (100 mg, 0.58 mmol, 0.1 eq) was added, and the mixture was refluxed at 120°C for 1.5 h. After the reaction, EA was added for dilution, and the mixture was washed with water and saturated brine for 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 812 mg of a white powdery solid with a yield of 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).

[0154] tert-Butyl 4-(hydroxy(5-(3-chloropyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)piperidine-1-carboxylate

[0155] 2-(3-chloropyridin-2-yl)-1,3,4-oxadiazole (251 mg, 1.38 mmol, 1 eq) was dissolved in anhydrous THF, and LDA (1 ml, 2.07 mmol, 1.5 eq) was slowly added at -78 °C. After stirring for 30 min, a THF solution of 1-Boc-4-piperidinecarboxaldehyde (295 mg, 1.38 mmol, 1 eq) was added, and then the temperature was raised to room temperature and the reaction was continued for 3 h. After the reaction was completed, a saturated ammonium chloride solution was added to quench, and then EA was used for extraction 3 times. The organic phases were combined, and then washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain 232.5 mg of solid with a yield of 42.60%. 1 H 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).

[0156] Piperidin-4-yl(5-(3-chloropyridinylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)methanone

[0157] Dess-Martin periodinane (474 ​​mg, 1.12 mmol, 2 eq) was added to a solution of tert-butyl 4-(hydroxy(5-(3-chloropyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)piperidine-1-carboxylate (220 mg, 0.56 mmol, 1 eq) in DCM, and the mixture was reacted at room temperature for 30 min. After the reaction was completed, a saturated sodium bicarbonate solution was added and stirred for 5 min, followed by extraction with EA 3 times, the organic phases were combined, and then washed with saturated sodium bicarbonate and saturated brine 3 times, respectively, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain a white powdery solid. The solid was dissolved in a hydrogen chloride-dioxane solution, reacted at room temperature for 30 min, and a solid precipitated. The solid was filtered and dried to obtain 47.7 mg of a light yellow solid with a yield of 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).

[0158] (5-Chloro-1-methyl-1H-indol-2-yl)(4-(5-(3-chloropyridin-2-yl)-1,3,4-oxadiazole-2-carbonyl)piperidin-1-yl)methanone (I-14)

[0159]

[0160] Referring to the synthesis method of (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone, 43 mg of a white solid was obtained with a yield of 64.95%. 1 H 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).

[0161] 2-(Furan-2-yl)-1,3,4-oxadiazole

[0162] 2-Furancarboxylic acid hydrazide (1.5 g, 11.89 mmol, 1 eq) was dissolved in trimethyl orthoformate, p-toluenesulfonic acid (200 mg, 1.2 mmol, 0.1 eq) was added, and the mixture was refluxed at 120°C for 1.5 h. After the reaction, EA was added for dilution, and the mixture was washed with water and saturated brine for 3 times, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 1.3 g of a colorless oily liquid with a yield of 80.3%. 1 HNMR (400MHz, DMSO) δ9.33 (s, 1H), 8.07 (s, 1H), 7.39 (d, J = 3.6Hz, 1H), 6.81 (d, J = 3.0Hz, 1H).

[0163] tert-Butyl 4-(hydroxy(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)piperidine-1-carboxylate

[0164] 2-(Furan-2-yl)-1,3,4-oxadiazole (1.3 g, 9.55 mmol, 1 eq) was dissolved in anhydrous THF, and LDA (7 ml, 14.33 mmol, 1.5 eq) was slowly added at -78 ° C. After stirring for 30 min, a THF solution of 1-Boc-4-piperidinecarboxaldehyde (2 g, 9.55 mmol, 1 eq) was added, and then the temperature was raised to room temperature and the reaction was continued for 3 h. After the reaction was completed, a saturated ammonium chloride solution was added to quench, and then EA was used for extraction 3 times, the organic phases were combined, and then washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain 918.8 mg of a yellow foamy solid with a yield of 27.53%. 1 H 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(d d,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).

[0165] tert-Butyl 4-(5-(furan-2-yl)-1,3,4-oxadiazole-2-carbonyl)piperidine-1-carboxylate

[0166] Dess-Martin periodinane (2.23 g, 5.26 mmol, 2 eq) was added to a solution of tert-butyl 4-(hydroxy(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)piperidine-1-carboxylate (918 mg, 2.63 mmol, 1 eq) in DCM, and the mixture was reacted at room temperature for 30 min. After the reaction, a saturated sodium bicarbonate solution was added and stirred for 5 min, followed by extraction with EA 3 times, the organic phases were combined, and then washed with saturated sodium bicarbonate and saturated brine 3 times, respectively, and dried over anhydrous sodium sulfate. Finally, 663 mg of a white powdery solid was obtained by column chromatography, with a yield of 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).

[0167] Piperidin-4-yl(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)methanone

[0168] 209 mg of tert-butyl 4-(5-(furan-2-yl)-1,3,4-oxadiazole-2-carbonyl)piperidine-1-carboxylate was dissolved in hydrogen chloride-dioxane solution and reacted at room temperature for 30 min. A large amount of light yellow solid precipitated, which was filtered and dried to obtain 170 mg of solid with a yield of 99.59%. 1 H 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=3.6,1.8H z,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).

[0169] (5-Chloro-1-methyl-1H-indol-2-yl)(4-(5-(furan-2-yl)-1,3,4-oxadiazole-2-carbonyl)piperidin-1-yl)methanone (I-15)

[0170]

[0171] Referring to the synthesis method of (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone, 70.1 mg of a white solid was obtained with a yield of 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).

[0172] 2-(Thiophen-2-yl)-1,3,4-oxadiazole

[0173] 2-Thiophenecarboxylic acid hydrazide (1.4 g, 9.85 mmol, 1 eq) was dissolved in trimethyl orthoformate, p-toluenesulfonic acid (170 mg, 0.99 mmol, 0.1 eq) was added, and the mixture was refluxed at 120°C for 1.5 h. After the reaction was completed, EA was added for dilution, and the mixture was washed with water and saturated brine for 3 times, 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%. 1 H 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).

[0174] tert-Butyl 4-(hydroxy(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)piperidine-1-carboxylate

[0175] 2-(Thiophene-2-yl)-1,3,4-oxadiazole (1.2 g, 7.89 mmol, 1 eq) was dissolved in anhydrous THF, and LDA (6 ml, 11.84 mmol, 1.5 eq) was slowly added at -78 °C, and a THF solution of 1-Boc-4-piperidinecarboxaldehyde (1.7 g, 7.89 mmol, 1 eq) was added after stirring for 30 min, and then the mixture was warmed to room temperature and the reaction was continued for 3 h. After the reaction was completed, a saturated ammonium chloride solution was added to quench the mixture, and the mixture was extracted with EA for 3 times, the organic phases were combined, and then washed with saturated brine for 3 times, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain 552.5 mg of a yellow foamy solid with a yield of 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).

[0176] tert-Butyl 4-(5-(thiophen-2-yl)-1,3,4-oxadiazole-2-carbonyl)piperidine-1-carboxylate

[0177] Dess-Martin periodinane (1.3 g, 3.02 mmol, 2 eq) was added to a solution of tert-butyl 4-(hydroxy(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)piperidine-1-carboxylate (552 mg, 1.51 mmol, 1 eq) in DCM and reacted at room temperature for 30 min. After the reaction, a saturated sodium bicarbonate solution was added and stirred for 5 min, followed by extraction with EA 3 times, the organic phases were combined, and then washed with saturated sodium bicarbonate and saturated brine 3 times, respectively, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain 496.6 mg of a yellow solid with a yield of 90.46%. 1 H 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).

[0178] Piperidin-4-yl(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methanone

[0179] 277 mg of tert-butyl 4-(5-(thiophen-2-yl)-1,3,4-oxadiazole-2-carbonyl)piperidine-1-carboxylate was dissolved in hydrogen chloride-dioxane solution and reacted at room temperature for 30 minutes. A large amount of light yellow solid precipitated. It was filtered and dried to obtain 195 mg of light yellow solid. The yield was 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).

[0180] (5-Chloro-1-methyl-1H-indol-2-yl)(4-(5-(furan-2-yl)-1,3,4-oxadiazole-2-carbonyl)piperidin-1-yl)methanone (I-16)

[0181]

[0182] Referring to the synthesis method of (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone, 90 mg of light yellow solid was obtained, with a yield of 58.69%. 1 H 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=5.0,3.7H z,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).

[0183] 6-Methoxypyridine-2-carboxylic acid hydrazide

[0184] Dissolve methyl 6-methoxy-2-pyridinecarboxylate (1.04 g, 6.22 mmol, 1 eq) in methanol, add hydrazine hydrate (374 mg, 7.46 mmol, 1.2 eq), stir at room temperature for 20 min, remove the solvent methanol by distillation under reduced pressure, add MTBE and stir for 15 min, filter to obtain a white powdery solid, dry in a vacuum oven, weigh 914 mg of a white powdery solid, and the yield is 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).

[0185] 2-(3-Methoxypyridin-2-yl)-1,3,4-oxadiazole

[0186] 6-Methoxypyridine-2-carboxylic acid hydrazide (893 mg, 5.34 mmol, 1 eq) was dissolved in trimethyl orthoformate, p-toluenesulfonic acid (92 mg, 0.53 mmol, 0.1 eq) was added, and the mixture was refluxed at 120°C for 1.5 h. After the reaction, EA was added for dilution, and the mixture was washed with water and saturated brine for 3 times, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain 796.7 mg of a white powdery solid with a yield of 84.18%. 1 H 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).

[0187] tert-Butyl 4-(hydroxy(5-(3-methoxypyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)piperidine-1-carboxylate

[0188] 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, 2.84 mmol, 2 eq) was slowly added at -78 ° C. After stirring for 30 min, a THF solution of 1-Boc-4-piperidinecarboxaldehyde (302 mg, 1.42 mmol, 1 eq) was added, and then the temperature was raised to room temperature and the reaction was continued for 3 h. After the reaction was completed, a saturated ammonium chloride solution was added to quench, and then EA was used for extraction 3 times, the organic phases were combined, and then washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and finally purified by column chromatography to obtain 248.5 mg of yellow oily droplets, with a yield of 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),4.4 7(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).

[0189] tert-Butyl 4-(5-(3-methoxypyridin-2-yl)-1,3,4-oxadiazole-2-carbonyl)piperidine-1-carboxylate

[0190] Dess-Martin periodinane (522 mg, 1.24 mmol, 2 eq) was added to a solution of tert-butyl 4-(hydroxy(5-(3-methoxypyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)piperidine-1-carboxylate (220 mg, 0.62 mmol, 1 eq) in DCM, and the mixture was reacted at room temperature for 30 min. After the reaction, a saturated sodium bicarbonate solution was added and stirred for 5 min, followed by extraction with EA for 3 times, the organic phases were combined, and then washed with saturated sodium bicarbonate and saturated brine for 3 times, respectively, and dried over anhydrous sodium sulfate. Finally, 149.1 mg of yellow oily droplets were obtained by column chromatography purification, with a yield of 62.45%. 1 H 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).

[0191] Piperidin-4-yl(5-(3-methoxypyridin-2-yl)-1,3,4-oxadiazol-2-yl)methanone

[0192] 140 mg of tert-butyl 4-(5-(3-methoxypyridin-2-yl)-1,3,4-oxadiazole-2-carbonyl)piperidine-1-carboxylate was dissolved in hydrogen chloride-dioxane solution and reacted at room temperature for 30 min. A large amount of light yellow solid precipitated, which was filtered and dried to obtain 112 mg of yellow solid. The yield was 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).

[0193] (5-Chloro-1-methyl-1H-indol-2-yl)(4-(5-(3-methoxypyridin-2-yl)-1,3,4-oxadiazole-2-carbonyl)piperidin-1-yl)methanone (I-17)

[0194]

[0195] Referring to the synthesis method of (5-chloro-1-methyl-1H-indol-2-yl)(4-isonicotinylpiperidin-1-yl)methanone, 111.8 mg of light yellow solid was obtained with a yield of 72.75%. 1 H 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).

[0196] (5-Chloro-1-methyl-1H-indol-2-yl)(4-(5-(3-methylpyridinyl)-1,3,4-oxadiazole-2-carbonyl)piperidin-1-yl)methanone (I-18)

[0197]

[0198] Referring to the synthesis method of I-1, 47 mg of white powdery solid was obtained with a yield of 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).

[0199] Example 2: In vitro FAAH enzyme inhibition activity test

[0200] FAAH can hydrolyze AEA to generate ethanolamine in cells. For a certain amount of reaction substrate, different enzyme activities catalyze the generation of different amounts of products. By detecting the amount of the product, the level of enzyme activity can be examined. The present invention is designed for experiments based on this principle. According to the FAAH kit instructions, a certain concentration of FAAH is diluted, a buffer solution and a fluorescently labeled reaction substrate are added, and then compounds of various concentrations are added, a blank control group and a JZL-195 positive control group are set, and fluorescence analysis is performed using an enzyme reader after the reaction is completed, and finally the inhibition rate is calculated.

[0201] The specific results are shown in the table:

[0202] Compound Name <![CDATA[IC 50 ]]> Control group: 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

[0203] As shown in the above table, the compounds of the present invention have good FAAH inhibitory activity.

[0204] Embodiment 3:

[0205] Anti-neuroinflammatory activity test of compound I-11

[0206] A neuroinflammation model was constructed using BV2 cells treated with LPS, and the release levels of inflammatory factors (TNF-α, IL-1β) were detected to investigate whether compound I-11 had an inhibitory effect on neuroinflammation. Figure 1 As shown in Table 1, in the cells of the Control group, the expression levels of inflammatory factors (TNF-α, IL-1β) were extremely low; after LPS treatment, the expression levels of TNF-α and IL-1β were significantly increased (p < 0.01); after LPS treatment, the expression levels of TNF-α and IL-1β were significantly increased (p < 0.01);

[0207] Inhibitor 1 can reduce the expression of inflammatory factors TNF-α and IL-1β in a dose-dependent manner when given cells pretreated with compound I-11. At high concentrations (20 μM), it can restore inflammatory factors to near normal levels. The experimental results show that compound 1 can effectively inhibit LPS-induced inflammatory response in BV2 cells, has good anti-neuroinflammatory response, and has the potential for further development.

[0208] Table 1 Anti-inflammatory activity test of compound I-11

[0209]

[0210] *p<0.01vs control group, # p<0.05vs LPS group, ## p<0.01vs LPS group.

[0211] The acetic acid writhing test in mice was used as a pain model to test the analgesic activity of compound I-11. The experimental animal information and experimental procedures are as follows.

[0212] a) Experimental animals

[0213] Healthy ICR mice, clean grade, weighing 20-25g. The animal room meets the requirements of clean laboratory, with a temperature of 20-22°C, a humidity of 40%-70%, and a controlled light / darkness of 12 hours per day and night (8:00-20:00 light hours). Mice were raised in plastic cages (volume 280×150×180mm), 10 per cage, males and females were raised separately, free to eat and drink water, feed was experimental mouse pellet feed, and drinking water was urban residents' drinking water after high temperature sterilization. The animal adaptation breeding time is 7 days. All treatments with animals follow the requirements of the Ethics Committee of the International Association for the Study of Pain. Mice were raised in the animal room after purchase.

[0214] b) Experimental drugs and reagents

[0215] Glacial acetic acid and physiological saline were purchased from the reagent library of China Pharmaceutical University. I-11 was a laboratory synthesized compound (purity>98%).

[0216] c) Test methods

[0217] The mice were marked with saturated picric acid solution, with the left forelimb being number 1, the left hindlimb being number 2, the right forelimb being number 3, the right hindlimb being number 4, and the head being number 5. The head plus the left forelimb was number 6, the head plus the left hindlimb was number 7, the head plus the right forelimb was number 8, the head plus the right hindlimb was number 9, and the tail was number 10. The animals were divided into groups, with n=10 in each group, half male and half female.

[0218] This experiment used the mouse writhing test to study the analgesic activity of the sample. Kunming mice weighing 20±2g were randomly divided into 4 groups, with 10 mice in each group. These included high, medium, and low dose groups of the sample and a control group. The sample was high (5mg·kg -1 ), medium (2.5 mg kg -1 ), low (1.25 mg kg -1 ) dose was administered subcutaneously to mice, and the control group was given an equal amount of normal saline (0.9% NaCl). 0.5 hour after administration, each mouse was intraperitoneally injected with 0.7% acetic acid (10 mL / kg). The number of writhing times and latency time of the mice 15 minutes after the injection of acetic acid were observed and recorded, the analgesic percentage was calculated, and statistical analysis was performed. The significance was determined by T test.

[0219] Analgesia percentage (%) = (average number of twists in the control group - average number of twists in the drug group) / average number of twists in the control group

[0220] Experimental results description

[0221] According to the acetic acid writhing test of mice, the number of writhing of mice in the blank control group, morphine group and I-11 group within 15 minutes was compared. -1 The inhibition rate of I-11 on mouse writhing reached 87.1%, indicating that compound I-11 has significant analgesic activity.

[0222] Inhibitory effect of different concentrations of compound I-11 on the number of writhings in mice

[0223]

[0224] Study on the antidepressant activity of compound I-11

[0225] Male SD rats weighing 180 g to 200 g were randomly divided into 6 groups, 8 rats in each group, as follows:

[0226] Normal group; Reserpine group; Positive control group (amitriptyline, 6 mg / kg); I-11 low-dose group (3 mg / kg); I-11 medium-dose group (6 mg / kg); I-11 high-dose group (12 mg / kg);

[0227] 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 the reserpine model was successfully established, the corresponding drugs were given according to the groups. After two weeks of continuous administration, the sugar water consumption test, open field test and forced swimming test were carried out in turn.

[0228] 1.1 Sugar water preference experiment

[0229] The American Psychiatric Association believes that an important feature of depression is a decrease in reward responsiveness, that is, a lack of pleasure. The sugar water preference test is a good evaluation indicator for detecting the reward responsiveness of experimental animals.

[0230] The results are as follows Figure 2 As shown in Table 2, compared with the blank group, the model group had a significantly lower sucrose drinking amount (p<0.01), indicating that the model group rats had obvious anhedonia symptoms, indicating that the depression model was successfully established; compared with the model group, the positive control group (amitriptyline) had a significantly higher sucrose drinking amount in the treatment group, indicating that the depression symptoms of the rats in the amitriptyline group were significantly alleviated. In addition, compared with the model group, the I-11 high-dose group had a significant difference (p<0.01) compared with the model group, and its effect was slightly lower than that of the positive control drug amitriptyline, indicating that compound I-11 has a certain antidepressant effect.

[0231] Table-2 Experimental study on sugar water preference

[0232]

[0233] *p<0.01vs control group, #p<0.01vs Model group.

[0234] 1.2 Open field experiment

[0235] After the sugar water preference experiment, we conducted an open field test on the test animals. Figure 3 As shown in Table 3, it was found that compared with the normal group, the central residence time of the rats in the model group in the open field test was significantly increased (p<0.01); in addition, the number of horizontal grids crossed, the number of times of standing upright, and the number of times of grooming were significantly reduced (p<0.01). Among them, the high-dose I-11 group had the same effect as the positive control amitriptyline group in the number of horizontal grids crossed, the number of times of standing upright, and the number of times of grooming, indicating that I-11 has a clear antidepressant effect.

[0236] Table 3 Open field experimental study

[0237]

[0238] *,P value compared to control group(*P<0.01); # ,P value compared to model group( # P<0.05, ## P<0.01).

[0239] 1.3 Forced swimming test

[0240] The results of the forced swimming test showed that compared with the normal group, the immobility time of the model group rats was significantly prolonged (p<0.01). After drug intervention, the amitriptyline group and the medium and high dose groups of I-11 could reduce the immobility time of the reserpine model rats (p<0.05). Among them, the effect of the high dose of I-11 (12 mg / kg) group was slightly lower than that of the amitriptyline group (6 mg / kg), indicating that compound 1 has a certain antidepressant potential. The results are shown in Table 4 below.

[0241] Table 4 Results of forced swimming test

[0242]

[0243] *,P value compared to control group(*P<0.01); # ,P value compared to model group( # P<0.05, ## P<0.01).

[0244] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof: in, Ar is selected from the following groups: R1 represents H or an aromatic ring or an aromatic heterocyclic ring, wherein the aromatic ring or aromatic heterocyclic ring is selected from The substituents on the aromatic ring or aromatic heterocyclic ring are selected from H, F, Cl, Br, I, methoxy, and methyl; L represents a connecting chain selected from -CO-; Selected from the following groups: R2 is selected from H, methyl; R3 is selected from H, F, Cl, Br, I.

2. A compound of formula I or a pharmaceutically acceptable salt thereof, characterized in that: The compound shown in formula I is selected from:

3. Use of the compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a medicament for preventing and / or treating a disease associated with FAAH.

4. The use according to claim 3, characterized in that: The diseases associated with FAAH include rheumatoid arthritis, hepatitis, liver fibrosis, autoimmune diseases, pain, depression, comorbid pain and depression, autism, social phobia, Tourette syndrome, neurodegenerative diseases, anxiety and post-traumatic stress, cannabinoid use disorders, drug withdrawal, and tumors.

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