Oxime compound as well as preparation and application thereof

Abstract

The invention relates to the field of medicinal chemistry, in particular to an oxime compound as well as preparation and application thereof, which not only selectively acts on a small molecule ligand of a Sigma-1 receptor, but also has low pharmacological toxicity. Neuropsychiatric disease treatment drugs on the market have been reported to act on the Sigma-1 receptor in a non-selective manner, however, no drugs which act on the Sigma-1 receptor in a selective manner successfully appear on the market so far. The disclosed aryl oxime compound is a Sigma-1 receptor ligand with selectivity, but the aryl oxime compound is used as a medicine, not only selectively acts on a Sigma-1 receptor, but also needs to have pharmacological safety. The oxime compound selectively acts on a small molecule ligand of a Sigma-1 receptor, is low in pharmacological toxicity and can be applied to preparation of various drugs for treating diseases of the central nervous system.

Description

Technical Field

[0001] The invention relates to the field of medicinal chemistry, and in particular to an oxime compound and preparation and application thereof, which not only selectively acts on a small molecule ligand of a Sigma-1 receptor but also has low pharmacological toxicity. Background Art

[0002] Sigma receptor is a membrane protein that can be divided into two subtypes: Sigma-1 and Sigma-2 receptors. Studies have found that Sigma-1 receptor is a binding protein for a variety of specific psychotropic drugs. As a receptor-type molecular chaperone, its physiological functions include: regulating ion channels (K + , Ca 2+ 、Na + Channels, etc.) and downstream receptors [inositol triphosphate (IP3) receptors, NMDAR, etc.], thereby regulating mitochondrial function and neurotransmitter release. The physiological functions of Sigma-1 receptors in the central nervous system mainly include improving drug addiction and movement disorders, protecting nerves, regulating cognition, etc., while peripheral Sigma-1 receptors are mainly distributed in lymphoid tissues, and their main function is to participate in regulating the body's immune function. Sigma-1 receptors are widely distributed in the central nervous system, with the most abundant being the hippocampus and thalamus, followed by the striatum, cerebellum, dorsal raphe nucleus, locus coeruleus, etc. They play an important regulatory role in the cholinergic, γ-aminobutyric acid (GABA) and dopamine nervous systems by regulating ion channels, neurotransmitter function and mitochondrial function, thereby exerting analgesic, memory impairment improvement, anti-epileptic, anti-depressant and neuroprotective effects.

[0003] To date, many marketed drugs for the treatment of neuropsychiatric diseases have been reported to act non-selectively on the Sigma-1 receptor, however, no drug that selectively acts on the Sigma-1 receptor has been successfully marketed. The applicant previously disclosed an aromatic oxime compound, which is a class of selective Sigma-1 receptor ligands, but as a drug, in addition to selectively acting on the Sigma-1 receptor, it also needs to have pharmacological safety. For this reason, the existing compound needs to be improved. Therefore, it is necessary to develop new oxime compounds, which are small molecule ligands that selectively act on the Sigma-1 receptor and have low pharmacological toxicity, which are of great significance for the treatment of neuropsychiatric diseases such as Alzheimer's disease, depression, epilepsy, Parkinson's disease, stroke, pain, and drug addiction. Summary of the invention

[0004] In order to solve the above technical problems, the purpose of the present invention is to provide an oxime compound, a pharmaceutically acceptable salt, ester or hydrate thereof, and its preparation and use. The oxime compound of the present invention selectively acts on the small molecule ligand of the Sigma-1 receptor and has low pharmacological toxicity, and can be used to prepare a variety of drugs for treating diseases of the central nervous system.

[0005] The present invention adopts the following technical scheme.

[0006] An oxime compound, the general chemical structure of which is as follows: ; Among them, R 1 is one or more selected from halogen alkyl, halogen acyl, alkoxy or halogen; R 2 is selected from an alkyl group, or forms a ring with Ar; Ar is selected from a benzene ring or an aromatic heterocycle; n is selected from 1 to 5; m and p are independently selected from 0 to 6; R 3 , R 4 One independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, methylsulfonyl, alkoxyalkyl, hydroxyl, hydroxyalkyl, deuterium, or both of them form a 3-8 membered ring with the C atom to which they are connected.

[0007] Preferably, R 1 One or more selected from trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethanesulfonyl, alkoxy or halogen, substituted with 1 to 3 substitutions; R 2 is selected from methyl, or forms a 4- to 8-membered ring with Ar; n is selected from any integer in the range of 1 to 3, such as 1, 2, and 3; m and p are independently selected from any integer in the range of 0 to 4, such as 0, 1, 2, 3, and 4; More preferably, n=1 or 2, m=p=2.

[0008] More preferably, when m=p=2, Ar is a benzene ring, R 3 and R 4 Not H at the same time.

[0009] In the present invention, halogen includes fluorine, chlorine and bromine.

[0010] The invention discloses the above oxime compounds and pharmaceutically acceptable salts, esters or hydrates thereof.

[0011] Furthermore, the pharmaceutically acceptable salt is a salt formed between the above-mentioned oxime compound and an inorganic acid or an organic acid, the pharmaceutically acceptable ester is an ester formed between the above-mentioned oxime compound and an acid (carboxylic acid or inorganic oxygen-containing acid) or an alcohol, and the pharmaceutically acceptable hydrate is a water-containing compound formed between the above-mentioned oxime compound and water by a coordinate bond or a covalent bond.

[0012] The present invention discloses a method for preparing the above oxime compounds, comprising the following steps: using chloride and amine as raw materials to react and prepare oxime compounds; The chemical structure of chloride is as follows: ; The general chemical structure of amine is as follows: .

[0013] In the present invention, the substituents and the number of repeating units in the chloride and amide are consistent with those in the oxime compound.

[0014] In the present invention, the reaction is carried out in the presence of an inorganic base, which includes potassium salts, sodium salts, calcium salts, etc., such as carbonates.

[0015] In the present invention, the reaction is carried out in an organic solvent, which is a conventional choice.

[0016] In the present invention, the reaction temperature is 70-100° C., and the reaction time is 0.5-5 hours; preferably, the reaction temperature is 80-90° C., and the reaction time is 1-3 hours.

[0017] In the present invention, the molar ratio of chloride to amide is 1:(1-3), preferably, the molar ratio of chloride to amide is 1:(1.5-2.5).

[0018] In the present invention, the molar ratio of chloride to inorganic base is 1:(1-3), preferably, the molar ratio of chloride to inorganic base is 1:(1.5-2.5).

[0019] The invention discloses a pharmaceutical composition, the active ingredients of which are the above oxime compounds, pharmaceutically acceptable salts, esters or hydrates thereof.

[0020] The invention discloses the application of the above oxime compounds, pharmaceutically acceptable salts, esters or hydrates thereof in the preparation of medicines.

[0021] The present invention discloses the use of the above-mentioned oxime compounds, and pharmaceutically acceptable salts, esters or hydrates thereof in the preparation of drugs for Sigma-1 related diseases.

[0022] The present invention discloses the use of the above-mentioned oxime compounds, pharmaceutically acceptable salts, esters or hydrates thereof as Sigma-1 ligands in the preparation of drugs for preventing and / or treating diseases related to Sigma-1.

[0023] Further, diseases associated with Sigma-1 include neuropsychiatric diseases.

[0024] Preferably, the neuropsychiatric disease includes epilepsy, depression, Alzheimer's disease, Parkinson's disease, ischemic stroke, neuropathic pain or drug addiction.

[0025] The purpose of the present invention is to provide an oxime compound, a pharmaceutically acceptable salt, ester or hydrate thereof, and the preparation and use thereof. The oxime compound of the present invention selectively acts on the small molecule ligand of the Sigma-1 receptor and has low pharmacological toxicity, especially, has a low hERG potassium ion channel inhibitory effect, IC 50 The value is as high as 21.59 uM, which also indicates that it has a low risk of cardiotoxicity and shows good cardiac safety. It can be used to prepare a variety of drugs for treating diseases of the central nervous system.

[0026] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the following is a detailed description of the preferred embodiments of the present invention in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The effects of compound C17 on cognitive function and spatial memory of normal mice, including familiarization stage (A), memory index (B) and (C). DETAILED DESCRIPTION

[0028] The purpose of the present invention is to provide an oxime compound, a pharmaceutically acceptable salt, ester or hydrate thereof, and the preparation and use thereof. The oxime compound of the present invention selectively acts on the small molecule ligand of the Sigma-1 receptor and has low pharmacological toxicity, especially, has a low hERG potassium ion channel inhibitory effect, IC 50 The value is as high as 21.59 uM, which also indicates that it has a low risk of cardiotoxicity and shows good cardiac safety. It can be used to prepare a variety of drugs for treating diseases of the central nervous system.

[0029] The present invention discloses an oxime compound and a pharmaceutically acceptable salt, ester or hydrate thereof. The general chemical structure formula of the oxime compound is as follows: ; Among them, R 1 is one or more selected from halogen alkyl, halogen acyl, alkoxy or halogen; R 2 is selected from an alkyl group, or forms a ring with Ar; Ar is selected from a benzene ring or an aromatic heterocycle; n is selected from 1 to 5; m and p are independently selected from 0 to 6; R 3 , R 4 One independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, methylsulfonyl, alkoxyalkyl, hydroxyl, hydroxyalkyl, deuterium, or both of them form a 3-8 membered ring with the C atom to which they are connected.

[0030] Preferably, R 1 One or more selected from trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethanesulfonyl, alkoxy or halogen, substituted with 1 to 3 substitutions; R 2 is selected from methyl, or forms a 4- to 8-membered ring with Ar; n is selected from any integer in the range of 1 to 3, such as 1, 2, 3; m and p are independently selected from any integer in the range of 0 to 4, such as 0, 1, 2, 3, 4; More preferably, n=1 or 2, m=p=2.

[0031] More preferably, when m=p=2, Ar is a benzene ring, R 3 and R 4 Not H at the same time.

[0032] In the present invention, halogen includes fluorine, chlorine and bromine.

[0033] The specific embodiments of the present invention are described in further detail below in conjunction with the accompanying drawings and examples. The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. The reagents used are all existing products, and the specific preparation operations and performance tests are all conventional techniques. Animal experiments meet the relevant requirements of Soochow University.

[0034] In the following embodiments of the present invention, the general preparation route of oxime compounds is as follows:

[0035] The specific general steps are as follows: Synthesis of oxime: Weigh the existing ketone (0.25 mmol) and dissolve it in ethanol (20 mL), add hydroxylamine hydrochloride (0.5 mmol) and potassium carbonate (0.5 mmol), and reflux at 90°C for 2 h. After the reaction, spin dry the solvent, dilute with water (15 mL), and then extract with dichloromethane (15 mL×2). The combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain oxime.

[0036] Synthesis of chloride: Weigh oxime (0.25 mmol) and dissolve it in dichloromethane (15 mL), add the corresponding halogenated alkane (1.25 mmol), CTMAB (hexadecyltrimethylammonium bromide 0.06 mmol) and 5N NaOH aqueous solution (5 ml), and reflux overnight at 50 ° C. After the reaction is completed, the solvent is spin-dried, diluted with water (15 mL), and then extracted with dichloromethane (15 mL×2), and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the chloride.

[0037] Synthesis of oxime compounds: Weigh the chloride (0.25 mmol) and dissolve it in acetonitrile (10 mL), add potassium carbonate (69 mg, 0.5 mmol) and the corresponding amide (0.5 mmol), and reflux at 85 ° C for 2 h. After the reaction is completed, the solvent is dried, diluted with water (15 mL), and then extracted with dichloromethane (15 mL × 2), the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is purified by silica gel column to obtain oxime compounds.

[0038] Embodiment 1 According to the general steps, the obtained （E） -1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime reacted with 4-fluoropiperidine to obtain compound C1, which was purified by silica gel column chromatography using an eluent (PE:EA = 3:1) to obtain a colorless oil with a yield of 68%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.75(d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 4.76 – 4.71 (m, 0.5H), 4.64 –4.59 (m, 0.5H), 4.25 (t, J = 6.4 Hz, 2H), 2.62 – 2.58 (m, 2H), 2.50 – 2.46(m, 2H), 2.43 – 2.38 (m, 2H), 2.23 (s, 3H), 1.98 – 1.85 (m, 6H). 13 C NMR (101MHz, CDCl 3 ) δ 153.3, 140.2, 130.9 (q, J C-F = 32.8 Hz), 126.4, 125.4 (q, J C-F =3.9 Hz), 124.2 (q, J C-F = 273.4 Hz), 73.8, 55.4, 49.8, 49.7, 31.7, 31.5, 27.1,12.7. HRMS (CI) calcd for C 17 H 22 F 4 N 2 O [M+H] +: 347.1747, found 347.1753.

[0039] According to the general steps, the obtained （E） -1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime reacted with 4-trifluoromethylpiperidine to obtain compound C2, which was purified by silica gel column chromatography using an eluent (PE:EA = 3:1) to obtain a colorless oil with a yield of 68%. Its H NMR spectrum, C NMR spectrum and mass spectrum results are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ7.75 (d, J = 7.0 Hz, 2H), 7.61 (d, J = 7.8 Hz, 2H), 4.26 (t, J = 5.2 Hz, 2H),3.03 (d, J = 8.9 Hz, 2H), 2.50 – 2.43 (m, 2H), 2.23 (s, 3H), 2.02 – 1.80 (m,8H), 1.76 – 1.52 (m, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 153.2, 140.2, 130.9 (q, J C-F = 97.0 Hz), 126.4, 125.4 (q, J C-F = 3.7 Hz), 124.9 (q, J C-F = 280.78 Hz),124.2 (q, J C-F = 272.7 Hz), 72.9, 55.4, 52.7, 40.6 (q, J C-F = 27.1 Hz), 27.1,24.8 (q, J C-F = 2.7 Hz), 12.6. LC-Ms: 369.2.

[0040] According to the general steps, the obtained （E）-1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime reacted with 4-methylpiperidine to obtain compound C3, which was purified by silica gel column chromatography using an eluent (PE:EA = 3:1) to obtain a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ 7.75 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.2Hz, 2H), 4.26 (t, J = 6.5 Hz, 2H), 2.52 – 2.47 (m, 6H), 2.23 (s, 3H), 1.96(p, J = 6.5 Hz, 2H), 1.41 (s, 4H), 0.26 (s, 4H). 13 C NMR (101 MHz, CDCl 3 ) δ153.2, 140.3, 130.8 (q, J C-F = 32.7 Hz), 126.4, 125.4 (q, J C-F = 3.9 Hz), 124.2(q, J C-F = 273.1 Hz), 73.2, 55.9, 53.5, 35.2, 27.1, 17.7, 12.6, 11.6. HRMS(CI) calcd for C 19 H 27 F 3 N 2 O [M+H] + : 354.1919, found 354.1917.

[0041] According to the general steps, the obtained （E） -1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime reacted with 4-difluoromethylpiperidine to obtain compound C4, which was purified by silica gel column chromatography using an eluent (PE:EA = 3:1) to obtain a colorless oil with a yield of 72%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ7.75 (d, J= 8.2 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 5.56 (td, J = 56.9, 4.5Hz, 1H), 4.25 (t, J = 6.4 Hz, 2H), 3.00 (d, J = 11.1 Hz, 2H), 2.61 – 2.38 (m,2H), 2.23 (s, 3H), 1.96 (d, J = 3.8 Hz, 1H), 1.91 (s, 2H), 1.83 – 1.69 (m,4H), 1.48 (q, J = 10.8, 9.0 Hz, 2H). LC-Ms: 378.2.

[0042] According to the general steps, the obtained （E） -1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime reacted with 4-cyanopiperidine to obtain compound C5, which was purified by silica gel column chromatography using an eluent (PE:EA = 3:1) to obtain a colorless oil with a yield of 65%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ7.75 – 7.71 (m, 2H), 7.61 – 7.56 (m, 2H), 4.23 (q, J = 6.0 Hz, 2H), 2.64 (s,3H), 2.48 – 2.43 (m, 2H), 2.33 (s, 2H), 2.24 – 2.17 (m, 3H), 1.88 (dt, J =11.9, 5.7 Hz, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 153.2, 140.2, 130.9 (q, J C-F =32.5 Hz), 126.3, 125.4 (q, J C-F = 3.8 Hz), 124.2 (q, J C-F= 271.9 Hz), 121.9,72.8, 55.4, 51.5, 28.9, 26.9, 26.3, 12.6. LC-Ms: 353.2.

[0043] According to the general steps, the obtained （E） -1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime reacted with 4-(methylsulfonyl)piperidine to obtain compound C6, which was purified by silica gel column chromatography using an eluent (PE:EA = 3:1) to obtain a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (500 MHz, CDCl 3 )δ 7.74 (d, J = 10.5 Hz, 2H), 7.68 (d, J = 10.5 Hz, 2H), 3.93 (t, J = 6.9 Hz,2H), 3.35 – 3.24 (m, 1H), 2.97 (s, 3H), 2.81 – 2.72 (m, 2H), 2.63 (t, J LC-Ms: 406.2 According to the general steps, the obtained （E） -1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime reacted with 4-methoxypiperidine to obtain compound C7, which was purified by silica gel column chromatography using an eluent (PE:EA = 3:1) to obtain a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ7.76 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 4.25 (t, J = 6.4 Hz, 2H), 3.34 (s, 3H), 3.22 (dt, J = 8.0, 4.4 Hz, 1H), 2.81 – 2.67 (m, 2H), 2.46 (t, J= 7.6 Hz, 2H), 2.23 (s, 3H), 2.13 (dd, J = 23.7, 13.8 Hz, 2H), 1.92 (q, J =6.8 Hz, 4H), 1.61 (q, J = 9.0 Hz, 2H). LC-Ms: 358.2.

[0044] According to the general steps, the obtained （E） -1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime reacted with 4-(methoxymethyl)piperidine to obtain compound C8, which was purified by silica gel column chromatography using an eluent (PE:EA = 3:1) to obtain a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 )δ 7.74 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 7.9 Hz, 2H), 4.24 (t, J = 6.2 Hz,2H), 3.32 (s, 3H), 3.21 (d, J = 6.4 Hz, 2H), 2.95 (d, J = 9.3 Hz, 2H), 2.51 –2.38 (m, 2H), 2.22 (s, 3H), 2.00 – 1.84 (m, 4H), 1.73 (d, J = 11.7 Hz, 2H), 1.65 – 1.52 (m, 1H), 1.37 – 1.19 (m, 2H). LC-Ms: 372.2.

[0045] According to the general steps, the obtained （E） -1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime reacted with 3-methoxypiperidine to obtain compound C9, which was purified by silica gel column chromatography using an eluent (PE:EA = 3:1) to obtain a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ7.75 (d, J = 8.1 Hz, 2H), 7.59 (d, J= 8.1 Hz, 2H), 4.24 (t, J = 6.4 Hz, 2H), 3.36 (s, 3H), 3.29 (dt, J = 8.2, 4.0 Hz, 1H), 2.90 (d, J = 8.5 Hz, 1H), 2.70– 2.59 (m, 1H), 2.53 – 2.44 (m, 2H), 2.22 (s, 3H), 2.13 – 2.00 (m, 2H), 1.93(dt, J = 13.2, 6.3 Hz, 3H), 1.75 (dd, J = 8.9, 4.3 Hz, 1H), 1.51 (dd, J =10.2, 3.3 Hz, 1H), 1.26 (q, J = 10.8, 9.3 Hz, 1H). LC-Ms: 358.2.

[0046] According to the general steps, the （E） -1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-bromoethyl)oxime reacted with 4-hydroxypiperidine to obtain compound C10, which was purified by silica gel column chromatography using an eluent (PE:EA = 3:1) to obtain a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum, and mass spectrum are as follows: 1 H NMR (600 MHz, CDCl 3 ) δ7.75 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 4.36 (t, J = 5.9 Hz, 2H), 3.71 (s, 1H), 2.86 (dt, J = 10.5, 4.5 Hz, 2H), 2.76 (t, J LC-Ms: 330.2.

[0047] According to the general steps, the （E）-1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime reacted with 4-hydroxypiperidine to obtain compound C11, which was purified by silica gel column chromatography using an eluent (PE:EA = 3:1) to obtain a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum, and mass spectrum are as follows: 1 H NMR (600 MHz, CDCl 3 ) δ7.75 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 4.25 (t, J = 6.4 Hz, 2H),3.76 (s, 1H), 2.89 – 2.78 (m, 2H), 2.54 (s, 2H), 2.23 (s, 3H), 1.98 (s, 4H),1.73 – 1.60 (m, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 156.1, 134.9, 132.6 (q, J =32.1 Hz), 127.4 (q, J = 1.9 Hz), 126.24(q, J = 4.1 Hz), 123.9 (q, J = 268.0Hz), 73.1, 67.5, 54.4, 50.6, 34.0, 25.0, 14.1.LC-Ms: calcd for C 17 H 23 F 3 N 2 O 2 [M]+: 344.1712, found 344.1718.

[0048] According to the general steps, the （E） -1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime reacted with 4-hydroxymethylpiperidine to obtain compound C12, which was purified by silica gel column chromatography using an eluent (PE:EA = 3:1) to obtain a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum, and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ7.75 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 4.24 (t, J= 6.3 Hz, 2H),3.48 (d, J = 6.2 Hz, 2H), 2.96 (d, J = 11.1 Hz, 2H), 2.53 – 2.40 (m, 2H), 2.23 (s, 3H), 1.94 (t, J = 7.7 Hz, 4H), 1.73 (d, J = 12.7 Hz, 2H), 1.50 (s,1H), 1.28 (q, J = 11.9 Hz, 2H). LC-Ms: 358.2.

[0049] According to the general steps, the （E） -1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime reacted with 2-hydroxymethylpiperidine to obtain compound C13, which was purified by silica gel column chromatography using an eluent (PE:EA = 3:1) to obtain a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum, and mass spectrum are as follows: 1 H NMR (500 MHz, CDCl 3 ) δ7.74 (d, J = 10.5 Hz, 2H), 7.68 (d, J = 10.5 Hz, 2H), 3.95 (t, J = 6.6 Hz,2H), 3.61 – 3.48 (m, 3H), 2.82 – 2.74 (m, 1H), 2.72 – 2.64 (m, 3H), 2.57 (dt, J = 12.5, 6.2 Hz, 1H), 2.31 (s, 3H), 1.90 – 1.73 (m, 3H), 1.61 – 1.41 (m,3H). LC-Ms: 358.2 According to the general procedure, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime was reacted with 4,4-dimethylpiperidine to obtain compound C14. Silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum results are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ7.75 (d, J= 8.2 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 4.25 (t, J = 6.3 Hz, 2H),2.65 – 2.41 (m, 6H), 2.23 (s, 3H), 1.98 (p, J = 6.5 Hz, 2H), 1.45 (t, J = 5.6Hz, 4H), 0.93 (s, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 153.3, 140.2, 130.9 (d, J C-F = 32.6 Hz), 126.4, 125.4 (d, J C-F = 3.8 Hz), 124.2 (d, J C-F = 272.1 Hz), 72.9,55.7, 50.1, 38.4, 28.5, 26.8, 12.6. LC-Ms: 356.2.

[0050] According to the general procedure, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime was reacted with 7-azaspiro[3.5]nonane to obtain compound C15. Silica gel column chromatography using eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 7.75 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H),4.24 (t, J = 6.4 Hz, 2H), 2.45 – 2.35 (m, 2H), 2.32 (s, 3H), 2.22 (s, 3H), 2.16 (s, 1H), 1.98 – 1.90 (m, 2H), 1.89 – 1.80 (m, 2H), 1.72 (t, J = 7.0 Hz,4H), 1.60 (t, J= 5.0 Hz, 4H). 13 C NMR (101 MHz, CDCl 3 ) δ 153.1, 140.3, 130.8(q, J C-F = 32.6 Hz), 126.4, 125.4 (q, J C-F = 3.8 Hz), 124.2 (q, J C-F = 272.0Hz), 73.2, 55.8, 50.7, 37.8, 37.8, 32.1, 27.2, 15.3, 12.6. LC-Ms: 368.2.

[0051] According to the general procedure, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime was reacted with 6-azaspiro[3.5]octane to obtain compound C16. Silica gel column chromatography using eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 )δ 7.75 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 4.26 (t, J = 6.4 Hz,2H), 2.55 – 2.38 (m, 6H), 2.23 (s, 3H), 1.96 (p, J = 6.5 Hz, 2H), 1.41 (s, 4H), 0.26 (s, 4H). 13 C NMR (101 MHz, CDCl 3 ) δ 153.2, 140.3, 130.8 (q, J C-F =32.5 Hz), 126.4, 125.4 (q, J C-F = 3.7 Hz), 124.2(q, J C-F = 272.0 Hz), 73.2,55.9, 53.5, 35.2, 27.1, 17.7, 12.6, 11.6. LC-Ms: 354.2.

[0052] According to the general procedure, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-bromoethyl)oxime was reacted with 4,4-difluoropiperidine to obtain compound C17. Silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ7.76 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 4.35 (t, J = 6.0 Hz, 2H),2.82 (t, J = 5.7 Hz, 2H), 2.68 (t, J = 5.7 Hz, 4H), 2.24 (s, 3H), 2.01 (tt, J = 12.9, 5.7 Hz, 4H). 13 C NMR (101 MHz, CDCl 3 ) δ 153.6, 140.0, 131.0 (q, J C-F =32.5 Hz), 126.4, 125.5(q, J C-F = 3.8 Hz),124.2(q, J C-F = 272.0 Hz), 122.0 (q, J C-F = 241.4 Hz), 72.8, 56.4, 50.5 (t, J C-F = 5.4 Hz), 34.2 (t, J C-F = 22.9 Hz),12.9. LC-Ms: 350.2.

[0053] According to the general procedure, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime was reacted with 4,4-difluoropiperidine to obtain compound C18. Silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl3 ) δ7.76 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 4.26 (t, J = 6.4 Hz, 2H),2.55 (dt, J = 14.4, 6.6 Hz, 6H), 2.24 (s, 3H), 2.12 – 1.85 (m, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 153.3, 140.2, 130.9 (q, J C-F = 32.5 Hz), 126.4, 125.4 (q, J C-F = 3.8 Hz), 124.2 (q, J C-F = 272.1 Hz), 122.2 (t, J C-F = 241.4 Hz),72.8,54.5, 50.2 (t, J C-F = 5.3 Hz), 34.2 (t, J C-F = 22.9 Hz), 27.3, 12.6. LC-Ms: 364.2.

[0054] According to the general procedure, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime was reacted with 2,2-dideuteropiperidine to obtain compound C19. Silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ7.75 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 4.26 (t, J = 6.2 Hz, 2H),2.73 – 2.52 (m, 4H), 2.23 (s, 3H), 2.10 (p, J = 6.5 Hz, 2H), 1.75 (s, 4H), 1.51 (s, 2H).13 C NMR (151 MHz, CDCl 3 ) δ 153.6, 140.1, 131.0 (d, J C-F = 32.4Hz), 126.4, 125.4 (q, J C-F = 3.8 Hz), 124.2 (q, J C-F = 271.8 Hz), 72.5, 55.9,54.3, 25.9, 24.9, 24.7, 23.7, 12.7. LC-Ms: 330.2.

[0055] According to the general procedure, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-bromoethyl)oxime was reacted with 8-oxa-2-aza[4.5]decane to obtain compound C20. Silica gel column chromatography using an eluent (PE:EA = 3:1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum results are as follows: 1 H NMR: 1 H NMR (600 MHz, CDCl 3 ) δ 7.76 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 4.36(t, J = 6.0 Hz, 2H), 3.64 (t, J = 5.3 Hz, 4H), 2.82 (t, J = 6.0 Hz, 2H), 2.70(t, J = 6.9 Hz, 2H), 2.55 (s, 2H), 2.25 (s, 3H), 1.70 (t, J = 6.9 Hz, 2H),1.62 (dt, J = 13.5, 5.5 Hz, 2H), 1.57 (dt, J = 13.3, 5.1 Hz, 2H). LC-Ms: 370.2.

[0056] According to the general procedure, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-bromoethyl)oxime was reacted with 7-oxa-2-aza[4.5]nonane to obtain compound C21. Silica gel column chromatography using an eluent (PE:EA = 3:1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum results are as follows: 1 H NMR (600 MHz, CDCl 3 ) δ 7.76 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 4.24 (t, J = 5.7Hz, 2H), 3.59 (t, J = 5.3 Hz, 24H), 3.14 (s, 4H), 2.83 (t, J = 5.8 Hz, 2H),2.24 (s, 3H), 1.76 (t, J = 5.3 Hz, 4H). LC-Ms: 356.2.

[0057] According to the general procedure, the obtained (E)-1-(4-(trifluoromethyl)phenyl)ethan-1-one O-(3-chloropropyl)oxime was reacted with 7-oxa-2-aza[4.5]nonane to obtain compound C22. Silica gel column chromatography using an eluent (PE:EA = 3:1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum results are as follows: 1 H NMR (500 MHz, CDCl 3 ) δ 7.74 (d, J = 10.5 Hz, 1H), 7.68 (d, J = 10.5 Hz, 1H), 3.93 (t, J =6.9 Hz, 1H), 3.61 (dd, J = 5.4, 2.7 Hz, 1H), 3.56 (dd, J = 5.4, 2.7 Hz, 1H),2.77 (s, 1H), 2.66 (t, J = 4.9 Hz, 1H), 2.64 (s, 1H), 2.31 (s, 1H), 1.83 (tt, J = 6.9, 4.8 Hz, 1H), 1.71 (dd, J= 5.5, 2.7 Hz, 1H), 1.63 (dd, J = 5.5, 2.6Hz, 1H). LC-Ms: 370.2.

[0058] According to the general procedure, the obtained (E)-6-(trifluoromethyl)-3,4-dihydronaphthalen-1(2H)-one O-(3-chloropropyl)oxime was reacted with piperidine to obtain compound C23. Silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum results are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ 8.04(d, J = 8.2 Hz, 1H), 7.43 – 7.37 (m, 2H), 4.26 (t, J = 6.1 Hz, 2H), 2.88 –2.68 (m, 10H), 2.26 – 2.15 (m, 2H), 1.92 – 1.79 (m, 6H), 1.64 – 1.50 (m, 2H). 13 C NMR (151 MHz, CDCl 3 ) δ 153.2, 139.9, 134.2, 130.6 (d, J C-F = 32.2 Hz),125.6 (d, J C-F = 4.1 Hz), 124.9, 124.2 (d, J C-F = 272.2 Hz), 123.1 (d, J C-F =3.9 Hz), 72.4, 55.9, 54.2, 29.8, 25.8, 24.7, 24.3, 23.6, 21.2. HRMS (CI)calcd for C 19 H 26 F 3 N 2 O [M+H] + : 355.1996, found 355.1997.

[0059] According to the general procedure, the obtained (E)-7-(trifluoromethyl)chromene-4-one O-(3-chloropropyl)oxime was reacted with piperidine to obtain compound C24, and silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum results are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ 7.99 (d, J =8.3 Hz, 1H), 7.18 – 7.11 (m, 2H), 4.23 (t, J = 6.3 Hz, 4H), 2.91 (t, J = 6.2Hz, 2H), 2.52 – 2.36 (m, 6H), 2.00 – 1.90 (m, 2H), 1.66 – 1.57 (m, 4H), 1.49– 1.40 (m, 2H). 13 C NMR (151 MHz, CDCl 3 ) δ 156.3, 147.1, 132.4 (q, J C-F = 32.8Hz), 125.0, 123.8 (q, J C-F = 273.3 Hz), 122.0, 117.8 (d, J C-F = 3.9 Hz), 115.2(q, J C-F = 4.1 Hz), 73.3, 65.3, 56.1, 54.7, 26.8, 25.9, 24.4, 23.9. HRMS (CI)calcd for C 18 H 24 F 3 N 2 O 2 [M+H] + : 357.1789, found 357.1790. HPLC: 99.7% (λ = 254nm, t R = 13.32 min).

[0060] According to the general procedure, the obtained (E)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one O-(3-chloropropyl)oxime was reacted with piperidine to obtain compound C25. Silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum results are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ 7.76(d, J = 8.1 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 4.23 (t, J = 6.3Hz, 2H), 3.14 – 3.03 (m, 2H), 2.97 – 2.85 (m, 2H), 2.57 – 2.35 (m, 6H), 1.97(q, J = 7.0 Hz, 2H), 1.68 – 1.58 (m, 4H), 1.50 – 1.41 (m, 2H). 13 C NMR (151MHz, CDCl 3 ) δ 161.2, 148.5, 140.0, 131.9 (d, J C-F = 32.0 Hz), 124.3 (d, J C-F =272.3 Hz), 124.2 (d, J C-F = 4.0 Hz), 122.7 (q, J C-F = 4.0 Hz), 121.9, 73.2,56.2, 54.8, 28.7, 27.0, 26.6, 26.1, 24.6. HRMS (CI) calcd for C 18 H 24 F 3 N 2 O [M+H] + :341.1839, found 341.1841. HPLC: 96.3% (λ = 254 nm, t R = 12.93 min).

[0061] According to the general procedure, the obtained (E)-1-(pyridin-2-yl)ethan-1-one O-(2-bromoethyl)oxime was reacted with piperidine to obtain compound C26. Silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.85 (d, J =4.9 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.92 (t, J = 6.9 Hz, 1H), 7.55 – 7.47(m, 1H), 4.66 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.83 – 2.75 (m,4H), 2.59 (s, 3H), 1.89 (p, J = 5.6 Hz, 4H), 1.71 (p, J = 6.1 Hz, 2H). LC-Ms:347.2.

[0062] According to the general procedure, the obtained (E)-1-(pyridin-2-yl)ethan-1-one O-(3-chloropropyl)oxime was reacted with piperidine to obtain compound C27, and silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 )δ 8.58 (d, J =5.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.28 – 7.19(m, 1H), 4.28 (t, J LC-Ms: 361.2.

[0063] According to the general procedure, the obtained (E)-1-(pyridin-4-yl)ethan-1-one O-(2-bromoethyl)oxime was reacted with piperidine to obtain compound C28, and silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum results are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ 8.55 (d, J =4.8 Hz, 2H), 7.47 (d, J = 5.1 Hz, 2H), 4.32 (t, J = 4.6 Hz, 2H),2.75 – 2.58(m, 2H), 2.48 – 2.37 (t, J = 5.4 Hz, 4H), 2.15 (s, 3H), 1.59 – 1.48 (m, 2H), 1.43 – 1.33 (m, 4H). LC-Ms: 347.2.

[0064] According to the general procedure, the obtained (E)-1-(pyridin-3-yl)ethan-1-one O-(2-bromoethyl)oxime was reacted with piperidine to obtain compound C29, and silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum results are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ 8.86 (s, 1H),8.58 (d, J = 4.5 Hz, 2H), 7.95 (d, J = 7.6 Hz, 2H), 7.40 – 7.25 (m, 1H), 4.36(t, J = 6.1 Hz, 2H), 2.72 (t, J LC-Ms: 347.2.

[0065] According to the general procedure, the obtained (E)-1-(pyrimidin-4-yl)ethan-1-one O-(2-bromoethyl)oxime was reacted with piperidine to obtain compound C30, and silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum results are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ 9.16 (s, 1H),8.63 (d, J = 5.3 Hz, 1H), 7.82 (d, J = 5.6 Hz, 1H), 4.39 (t, J = 6.0 Hz, 2H),2.72 (t, J LC-Ms: 348.2.

[0066] According to the general procedure, the obtained (E)-1-(6-(trifluoromethyl)pyridin-3-yl)ethan-1-one O-(2-bromoethyl)oxime was reacted with piperidine to obtain compound C31. Silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ 8.96(s, 1H), 8.11(d, J = 7.7 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 4.39 (t, J = 6.0Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.50 (t, J = 5.3 Hz, 4H), 2.25 (s, 3H), 1.61 (p, J = 5.5 Hz, 4H), 1.43 (p, J = 5.7 Hz, 2H). LC-Ms: 315.2.

[0067] According to the general procedure, the obtained (E)-1-(6-(trifluoromethyl)pyridin-3-yl)ethan-1-one O-(3-chloropropyl)oxime was reacted with piperidine to obtain compound C32. Silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ 8.94(s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 4.25 (t, J LC-Ms: 329.2.

[0068] According to the general procedure, the obtained (E)-1-(5-(trifluoromethyl)pyridin-2-yl)ethan-1-one O-(2-bromoethyl)oxime was reacted with piperidine to obtain compound C33. Silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (600 MHz, CDCl 3 ) δ 8.82– 8.79 (m, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.86 – 7.81 (m, 1H), 4.41 (t, J =6.0 Hz, 2H), 2.77 (t, J = 6.0 Hz, 2H), 2.60 – 2.47 (m, 4H), 2.30 (s, 3H), 1.61 (p, J = 5.6 Hz, 4H), 1.43 (p, J = 6.0 Hz, 2H). LC-Ms: 315.2.

[0069] According to the general procedure, the obtained (E)-1-(5-(trifluoromethyl)pyridin-2-yl)ethan-1-one O-(3-chloropropyl)oxime was reacted with piperidine to obtain compound C34. Silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, DMSO- d 6 ) δ8.83 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.4 Hz, 1H), 4.29 (t, J = 6.1 Hz, 2H), 2.50 (q, J = 7.2, 5.5 Hz, 9H), 2.31 (s, 3H), 2.01 (p, J = 6.5Hz, 3H), 1.74 – 1.57 (m, 5H), 1.54 – 1.40 (m, 3H). LC-Ms: 329.2.

[0070] According to the general procedure, the obtained (E)-1-(quinolin-6-yl)ethan-1-one O-(3-chloropropyl)oxime was reacted with piperidine to obtain compound C35. Silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (300 MHz, CDCl 3 ) δ 8.91 (d, J =4.3 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 8.09 (q, J = 8.9 Hz, 2H), 7.99 (s,1H), 7.42 (dd, J = 8.4, 4.3 Hz, 1H), 4.31 (t, J LC-Ms: 311.2.

[0071] According to the general procedure, the obtained (E)-1-(quinolin-6-yl)ethan-1-one O-(2-bromoethyl)oxime was reacted with piperidine to obtain compound C36. Silica gel column chromatography using an eluent (PE: EA = 3: 1) gave a colorless oil with a yield of 70%. Its H NMR spectrum, C NMR spectrum and mass spectrum are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (dd, J =4.3, 1.7 Hz, 1H), 8.19 – 8.11 (m, 1H), 8.10 (dd, J = 8.9, 2.0 Hz, 1H), 8.03(d, J = 8.9 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.3, 4.3 Hz,1H), 4.56 (t, J = 5.4 Hz, 2H), 3.05 (t, J = 5.4 Hz, 2H), 2.87 – 2.77 (m, 4H), 2.31 (s, 3H), 1.80 (p, J = 5.4 Hz, 4H), 1.56 – 1.45 (m, 2H). LC-Ms: 297.2.

[0072] The chemical structural formula of the above product is shown in Table 1, the left part of which comes from the raw material ketone, and C=N is replaced by C=O.

[0073] Embodiment 2 The biological activity test of the compound prepared above is carried out as follows: The protein was diluted to 200 mg / mL with Kreb's solution. The radioligand of membrane protein Sigma-1 ligand is 3 H(+)-pentazocine. The reaction system consists of 100 μL membrane protein, 20 μL 3 H(+)-pentazocine, 20μL of the test drug and 60μL of Kreb's solution. After incubation at 30℃ for 150 minutes, the free radioactive ligand and the radioactive ligand bound to the receptor were separated by filtration. The activity of the isotope bound to the receptor was detected by liquid scintillation. 10μM BD1047 was used to determine the nonspecific binding activity. The specific binding activity without the addition of the test compound was defined as 100%.

[0074] As shown in Table 1, at a concentration of 10 μM, if the compound's inhibition rate on the binding of radioligand to Sigma-1 receptor is less than 50%, it is considered that the compound has no affinity for Sigma-1 receptor. For compounds with an inhibition rate higher than 85%, further tests were conducted on the compound's inhibition rate on the binding of radioligand to Sigma-1 receptor and K at a concentration of 1 μM. i The results show that the substituent (R 3 and R 4 ) and the length of the intermediate carbon chain (n) both affect the affinity of the compound to sigma-1. Among them, compounds C1, C3, C4, C6, C12, C13, C17, C20, C27, C29, C31 and C35 have a Ki of less than 30 nM for the sigma-1 receptor, showing a strong affinity.

[0075] Select compounds with high affinity for Sigma-1 receptor for Sigma-2 receptor binding assay. The procedure is similar to that for Sigma-1 receptor: Sigma-2 receptor labeling ligand is 3 H-DTG. 10 μM BD1047 was added to the reaction system to block the binding activity of Sigma-1. 10 μM haloperidol was used to determine the nonspecific binding activity. The specific binding activity without the addition of the test compound was defined as 100%. If the compound has an inhibition rate of more than 75% on the binding of the radioligand to the sigma-2 receptor at a concentration of 10 μM, the compound is considered to have a low affinity for the sigma-2 receptor. The results are shown in Table 2, and the compounds all showed excellent sigma-2 receptor selectivity.

[0076] When the benzene ring of the compounds in Table 1 was replaced with a heterocyclic ring, it was found that the compounds also exhibited high sigma-1 receptor affinity and selectivity.

[0077] Table 1 Sigma-1 receptor affinity test results of different compounds ; ;

[0078] Table 2 Sigma-1 receptor affinity test results of different compounds

[0079] Example 3 Functional determination of small molecule ligands of sigma-1 receptor The ability of the sigma-1 receptor allosteric modulator phenytoin to differentially modulate the affinity of sigma-1 ligands will be utilized in the radiolabeled receptor affinity assay described above to determine the function of the compound, i.e., sigma-1 receptor agonist or antagonist. In general, phenytoin (250 μM) enhances the receptor binding affinity of sigma-1 agonists, i.e., the K of phenytoin is not i / K containing phenytoin i >1, it is a sigma-1 receptor agonist; phenytoin (250 μM) has no effect on or slightly reduces the receptor binding affinity of sigma-1 antagonists, that is, it does not contain phenytoin's K i / K containing phenytoin i ≤1, it is a sigma-1 receptor antagonist. As shown in Table 3, C9, C6, C12, C17, C25, C27, C28, C31 and C35 are sigma-1 receptor agonists, which have potential therapeutic effects on Alzheimer's disease, schizophrenia, depression, anxiety, Parkinson's disease, drug addiction, movement disorders caused by anti-Parkinson's disease / schizophrenia drugs, and cognitive impairment caused by neuropsychiatric diseases, and also have a nootropic effect. On the other hand, C2, C29 and C36 are sigma-1 receptor antagonists and are expected to be potential analgesics.

[0080] Table 3 Functional assays of small molecule ligands of sigma-1 receptor

[0081] Example 4 Determination of hERG potassium channel inhibition rate experiment The fully automated electrophysiological patch clamp QPatch was used to detect the inhibitory effect of compound S4 on the hERG potassium channel. The specific operation is as follows: The cells used in this experiment are CHO cell lines transfected with hERG cDNA and stably expressing hERG channels (provided by Sophion Bioscience), and the cell generation is P30. After reaching the whole-cell configuration state of membrane rupture in the initial stage, the cells were recorded for 120 seconds to achieve stability. Then throughout the process, the cells were clamped at a voltage of -80 mV. The cell clamping voltage was depolarized to +20 mV to activate the hERG potassium channel, and then clamped to -50 mV after 2.5 seconds to eliminate inactivation and generate outward tail current. The above voltage mode was applied to the cells every 15 seconds. Only stable cells were allowed to enter the drug treatment process in the above parameter threshold recording. An external solution containing 0.1% dimethyl sulfoxide (solvent) was applied to the cells to establish a baseline, and the current was allowed to stabilize for 3 minutes. After the compound is added, the cells are kept in the test environment until the effect of the compound reaches a steady state or within 4 minutes. In the test experiment with different concentration gradients of the compound, the compound is added to the clamped cells from low to high concentrations. After the compound test is completed, the cells are washed with external fluid until the current returns to a steady state. The positive control (cisapride) is used in the experiment to ensure normal cell response and reliable cell quality. Unless otherwise specified, the experiments are carried out at normal room temperature (~25 ℃). The experimental data are analyzed by Qpatch analysis software, Excel, etc. provided by Sophion.

[0082] The test results show that the representative compound B1 (IC 50 value is 0.95uM), D1 (IC 50 The compound of the present invention has a lower hERG potassium channel inhibitory effect, IC 50 The value is 2.10-21.59 uM, which also indicates that its risk of cardiotoxicity is low and shows better cardiac safety.

[0083]

[0084] Example 5 Compound New Object Recognition Experiment The novel object recognition test (NOR) is an experimental method to evaluate the cognitive memory level of animals by the time they explore old (previously encountered) objects and new (never encountered) objects. The details are as follows: Place the mouse in an experimental device without objects at the same position and let it move freely for 10 minutes. No video is recorded during this stage. Two identical objects A and B are placed symmetrically, and the objects are about 10 cm away from the four walls to ensure that the experimental animals have sufficient space for exploration. The exploration standard is to touch the object with the mouth or nose or get close to the object within about 2-3 cm. Record the video for 10 minutes and count the exploration time of the mouse for the two objects in this stage within 10 minutes. No video is recorded at this stage. Only books or special isolation tools are used to isolate the mouse and make it forget the event it just experienced. The time is 5 minutes. Replace one of the objects with an object of completely different shape and color. Place the mouse in the device at the same position and let it move freely for 10 minutes. Count the exploration time of the mouse for the new object and the old object in this stage within 10 minutes. The exploration time of new objects and old objects during the test period was statistically calculated, that is, (Exploration time). The memory index (Preference ratio) = (Exploration time of new objects - Exploration time of old objects) / (Exploration time of new objects + Exploration time of old objects), that is, (NF) / (N+F).

[0085] like Figure 1 As shown, in order to explore the effects of C17 on cognitive function and spatial memory in normal mice, the doses of 3 mg / kg and 10 mg / kg were selected to conduct novel object recognition test (NOR) and Morris water maze test (MWM). In the novel object recognition test: familiarization stage ( Figure 1 A) There was no difference in the time mice spent exploring the two identical objects, indicating that the experimental mice themselves had no location preference. In the test phase, there was a significant difference in the time mice spent exploring the new and old objects, such as Figure 1 As shown in B, it shows that the cognitive ability of mice in each group is normal, which is manifested by spending more time exploring new objects. Figure 1 B) and ( Figure 1 C) index, both drug-treated groups (3 mg / kg, 10 mg / kg) were significantly higher than the control group ( P <0.0001 vs. VEH group). The results showed that 3 mg / kg and 10 mg / kg of C17 could improve the cognitive ability of mice.

[0086] In summary, most of the compounds showed moderate to high activity on the Sigma-1 receptor and lower activity on the Sigma-2 receptor, especially compound C17 and the like showed high affinity for the Sigma-1 receptor and almost no activity on the Sigma-2 receptor. This indicates that the present invention provides a class of Sigma-1 receptor ligands with a new structure and high selectivity. Such oxime compounds will be of great significance for the treatment of diseases of the central nervous system, such as Alzheimer's disease, schizophrenia, depression, anxiety, Parkinson's disease, pain, drug addiction, movement disorders caused by anti-Parkinson's disease / schizophrenia drugs, and cognitive impairment caused by neuropsychiatric diseases.

[0087] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. It should be pointed out that a person skilled in the art can make several improvements and modifications without departing from the technical principles of the present invention, and these improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. An oxime compound, or a pharmaceutically acceptable salt, ester or hydrate of the oxime compound, characterized in that: The chemical structure formula of the oxime compound is as follows: ； Among them, R1 is selected from one or more of halogen alkyl, halogen acyl, alkoxy or halogen; R2 is selected from alkyl, or forms a ring with Ar; Ar is selected from a benzene ring or an aromatic heterocycle; n is selected from 1 to 5; m and p are independently selected from 0 to 6; R3 and R4 are independently selected from one of hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, methylsulfonyl, alkoxyalkyl, hydroxyl, hydroxyalkyl, deuterium, or both form a 3-8 membered ring with the C atom to which they are connected.

2. The oxime compound according to claim 1, characterized in that: R1 is selected from one or more of trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethanesulfonyl, alkoxy or halogen, and the substitution is 1 to 3 substitutions; R2 is selected from methyl, or forms a 4 to 8 membered ring with Ar; n is selected from any integer from 1 to 3; m and p are independently selected from any integer from 0 to 4.

3. The oxime compound according to claim 2, characterized in that: n=1 or 2, m=p=2.

4. The oxime compound according to claim 3, characterized in that: When m=p=2 and Ar is a benzene ring, R3 and R4 are not H at the same time.

5. The method for preparing the oxime compound according to claim 1, comprising the following steps: Using chloride and amine as raw materials, oxime compounds are prepared by reaction; The chemical structure of chloride is as follows: ； The general chemical structure of amine is as follows: 。 6. The method for preparing oxime compounds according to claim 5, characterized in that: The reaction is carried out in an organic solvent in the presence of an inorganic base; the reaction temperature is 70-100° C. and the reaction time is 1-3 hours.

7. The method for preparing oxime compounds according to claim 5, characterized in that: The molar ratio of chloride to amine is 1:(1-3).

8. A pharmaceutical composition, the active ingredient of which is the oxime compound according to claim 1, or a pharmaceutically acceptable salt, ester or hydrate thereof.

9. Use of the oxime compound according to claim 1, or a pharmaceutically acceptable salt, ester or hydrate thereof in the preparation of a drug.

10. Use of the oxime compound according to claim 1, or a pharmaceutically acceptable salt, ester or hydrate thereof in the preparation of drugs for Sigma-1 related diseases.

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