TRPV3 inhibitor and preparation and application thereof

Abstract

The invention provides a compound as shown in a general formula (I) as a TRPV3 inhibitor or a pharmaceutically acceptable salt thereof and a preparation method thereof. The compound or the pharmaceutically acceptable salt thereof can be used for treating or preventing TRPV3-related skin diseases. The present invention also provides a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof, and uses of the compound or the pharmaceutically acceptable salt thereof in the treatment of TRPV3-related skin diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to TRPV3 inhibitor compounds, methods for their preparation, pharmaceutical compositions comprising such compounds, and the use of such compounds in the treatment of diseases. Specifically, the present invention relates to aryl ring-fused imidazole derivatives that can be used as TRPV3 inhibitors, methods for their preparation, pharmaceutical compositions comprising such derivatives, and the use of aryl ring-fused imidazole derivatives in the treatment of TRPV3-related skin diseases. Background Art

[0002] Transient receptor potential (TRP) channels, as a family of non-selective cation channels, were first discovered by Cosen et al. in Drosophila photoreceptor cells in 1969. There are 28 members of mammalian TRP channels, which are divided into 7 subgroups according to amino acid sequence homology: TRPC (Canonical), TRPV (Vanilloid), TRPM (Melastatin), TRPP (Polycystin), TRPA (Ankyrin), TRPML (Mucolipin), and TRPN (NOMPC-like). These channels are activated through various mechanisms and are involved in almost all sensory modalities.

[0003] The TRPV subfamily of transient receptor potential consists of 6 members: TRPV1 to TRPV6. All 6 TRPV subfamily members have ankyrin repeat domains at the N-terminus. The 33 residues that make up each ankyrin repeat sequence usually serve as important motifs for subunit-subunit interactions. Among the 6 subfamily members, TRPV1, TRPV2, TRPV3, and TRPV4 are temperature-sensitive channels with appropriate Ca 2+ permeability, and TRPV5 and TRPV6 are highly selective channels for Ca 2+ As temperature-sensitive channels with appropriate Ca 2+ permeability, TRPV3 has high homology with TRPV2, TRPV1, and TRPV4: 42% homology with TRPV1, 43% homology with TRPV2, and 41% homology with TRPV4.

[0004] Structurally, TRPV3 has a cytoplasmic amino terminus and carboxyl terminus, ankyrin repeat sequences, an amino-terminal helix-helix domain, 6 transmembrane segments, a re-entrant pore loop, and many potential phosphorylation sites. Compared with the ankyrin repeat domains of TRPV1 and TRPV4, TRPV3 is considered to have 6 ankyrin repeat sequences, with an insertion in repeat 1 and 2 short deletions in repeats 4 and 5. Moreover, TRPV3 has a unique bent finger 3 loop, which is maintained through hydrogen bonding and hydrophobic packing.

[0005] TRPV3 is most highly expressed in human and murine skin keratinocytes and oral and nasal epithelia, and is also expressed in a variety of cells such as the brain, spinal cord, DRG, TG, and testis. TRPV1 is expressed in sensory neurons. More specifically, TRPV1 is expressed in approximately half of somatic and visceral sensory neurons, and the expression is limited to small to medium-sized neurons in the dorsal root, trigeminal ganglion, and vagal ganglion. Additionally, TRPV1 is also expressed in perivascular sensory neurons and regulates vasodilation. TRPV1 expressed in arteriolar smooth muscle may control blood flow in skeletal muscle and certain thermoregulatory tissues such as the skin, trachea, and cremaster muscle. TRPV2 is highly expressed in the brain, lung, and spleen, and is also expressed in endocrine cells, epithelial cells, immune cells, and cardiomyocytes. In addition, TRPV2 is expressed in multiple regions of the brain. TRPV4 is widely expressed in numerous tissues.

[0006] Compared with TRPV1, the most studied member of the TRPV family, the development of TRPV3 has been slow due to the lack of effective and selective agonists or inhibitors. With the analysis of the cryo-electron microscopy structure of TRPV3, new opportunities for the study of TRPV3 have been provided. However, most of the initial TRPV3 inhibitors were natural products with large effective doses and may cause serious side effects. Subsequently, three companies, Glenmark Pharmaceuticals, Hydra Biosciences, and Abbvie Inc., began to develop small molecule inhibitors of TRPV3, but the existing TRPV3 inhibitors still have problems such as insufficient effectiveness and poor selectivity.

[0007] Therefore, there remains a need for effective TRPV3 inhibitors, especially specific TRPV3 inhibitors that are highly selective relative to other TRP channels such as TRPV1, TRPV4, and TRPA1. Summary of the Invention

[0008] In a first aspect, the present invention provides a small molecule inhibitor of TRPV3, which is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

[0009]

[0010] Wherein:

[0011] R1 can be selected from hydrogen, hydroxyl, -C(=O)-NR'2, -S(=O)2-R', -S(=O)2-NR'2, C1-C6 alkyl, halo C 1-6 alkyl, C1-C6 alkoxy, phenyl, benzyl, 5-6 membered heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocyclic group, and C9-C 10Fused bicyclic heteroaryl, wherein R' is independently H or C1-C3 alkyl, said 5-6 membered heteroaryl, C3-C7 heterocyclic group and C9-C 10 The fused bicyclic heteroaryl may contain 1 or 2 heteroatoms independently selected from N, O and S and may optionally be oxo, and R1 may optionally be substituted by one or more groups independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkylamino, di-C1-C3 alkylamino, acetylamino, N-methyl-N-acetylamino and 5-6 membered cyclic amino groups;

[0012] R2 may be selected from phenyl, 5-6 membered heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocyclic group, wherein said 5-6 membered heteroaryl and C3-C7 heterocyclic group may contain 1 or 2 heteroatoms independently selected from N, O and S and may optionally be oxo, and R2 may optionally be substituted by one or more substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkylamino, di-C1-C3 alkylamino, acetylamino, N-methyl-N-acetylamino or 5-6 membered cyclic amino group;

[0013] R3 may be selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen, cyano, nitro, amino, -S(=O)2-R' and -S(=O)2-NR'2, wherein R' is independently H or C1-C3 alkyl;

[0014] W and X are each independently selected from N and C;

[0015] Z may be selected from -CH2-, -CH2-CH2- and -C(=O)-, and Z may optionally be substituted by one or more groups independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkylamino, di-C1-C3 alkylamino, acetylamino, N-methyl-N-acetylamino or 5-6 membered cyclic amino group; and

[0016] Y may be selected from -O-, -S-, -NH- and -N(C1-C3 alkyl)-.

[0017] In one embodiment, in general formula (I), R1 may be selected from hydrogen, hydroxy, -S(=O)2-R', -S(=O)2-NR'2, phenyl, benzyl, pyridyl, benzothiazolyl, C 1-3Alkyl, C 3-7 Cycloalkyl, halo C 1-3 Alkyl and C 1-3 Alkoxy, where R’ is independently H or C1-C3 alkyl, and R1 may optionally be substituted by one or more substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkylamino.

[0018] In this embodiment, R2 may be selected from phenyl and 5-6 membered heteroaryl, where the 5-6 membered heteroaryl may contain 1 or 2 heteroatoms independently selected from N, O, and S and is optionally oxo, and R2 may optionally be substituted by one or more substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkylamino.

[0019] Preferably, R2 may be selected from phenyl and 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, N, and S, and R2 may optionally be substituted by 1-3 substituents independently selected from halogen, cyano, C 1-3 Alkyl, halo C 1-3 Alkyl, C 1-3 Alkoxy.

[0020] In this embodiment, R3 may be selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, -S(=O)2-R’, -S(=O)2-NR’2, C 1-3 Alkyl, halo C 1-3 Alkyl, C 1-3 Alkoxy, where R’ is independently H or C1-C3 alkyl.

[0021] In this embodiment, W and X are each independently selected from N and C.

[0022] In this embodiment, Z may be selected from -CH2-, -CH2-CH2-, -C(=O)-, and -CH(OH)CH2-.

[0023] In this embodiment, Y may be selected from -O-, -S-, and -NH-.

[0024] In another embodiment, in general formula (I), R1 may be selected from hydrogen, C1-C6 alkyl, halo C1-C6 alkyl, phenyl, benzyl, 5-6 membered heteroaryl, C3-C7 cycloalkyl, and C9-C 10 Fused bicyclic heteroaryl, the 5-6 membered heteroaryl, C3-C7 heterocyclic group, and C9-C 10The fused bicyclic heteroaryl contains 1 or 2 heteroatoms independently selected from N, O, and S, and R1 may optionally be substituted by one or more groups independently selected from hydroxy, halogen, amino, cyano, and nitro.

[0025] Preferably, R1 may be selected from halo C1-C6 alkyl, phenyl, benzyl, 5- or 6-membered heteroaryl, C3-C7 cycloalkyl, and C9-C 10 fused bicyclic heteroaryl, said 5- or 6-membered heteroaryl, C3-C7 heterocyclic group, and C9-C 10 The fused bicyclic heteroaryl may contain 1 or 2 heteroatoms independently selected from N, O, and S, and R1 may optionally be substituted by cyano. More preferably, R1 may be selected from trifluoromethyl, phenyl, benzyl, pyridyl, cyclopentyl, and benzothiazolyl, and R1 may optionally be substituted by cyano. Even more preferably, R1 may be trifluoromethyl.

[0026] In this embodiment, R2 may be selected from phenyl and 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S, and R2 may optionally be substituted by one or more substituents independently selected from hydroxy, halogen, amino, C1-C3 alkylamino, di-C1-C3 alkylamino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, and. Preferably, R2 may be selected from phenyl, pyridyl, and pyrimidinyl, and R2 may optionally be substituted by one or more substituents independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, and halo C1-C3 alkyl. More preferably, R2 may optionally be substituted by one or more substituents independently selected from C1-C3 alkyl and halo C1-C3 alkyl. Even more preferably, R2 may optionally be substituted by methyl or trifluoromethyl.

[0027] In this embodiment, R3 may be selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen, cyano, nitro, amino, -S(=O)2-R', and -S(=O)2-NR'2, where R' is independently H or C1-C3 alkyl. Preferably, R3 may be selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen, cyano, -S(=O)2-C1-C3 alkyl, and -S(=O)2-NH2. More preferably, R3 may be selected from C 1-6 alkyl, halo C 1-6 alkyl, halogen, and cyano. Even more preferably, R3 may be selected from C 1-3 alkyl, fluoro C 1-3 alkyl, halogen, and cyano.

[0028] In this embodiment, W and X are each independently selected from N and C.

[0029] In this embodiment, Z may be selected from -CH2-, -CH2-CH2-, and -C(=O)-, and Z may optionally be substituted by one or more hydroxyl groups. Preferably, Z may be selected from -CH2-, -CH2-CH2-, -CH(OH)-CH2-, and -C(=O)-. More preferably, Z may be -CH2-.

[0030] In this embodiment, Y may be selected from -O-, -S-, and -NH-. Preferably, Y may be selected from -O- and -NH-. More preferably, Y may be -O-.

[0031] In yet another embodiment, in general formula (I), R1 may be a halogenated C1-C6 alkyl group. Preferably, R1 may be a fluorinated C1-C3 alkyl group. More preferably, R1 may be trifluoromethyl.

[0032] In this embodiment, R2 may be selected from phenyl and pyridyl, and R2 may optionally be substituted by one or more substituents independently selected from C1-C3 alkyl groups and halogenated C1-C3 alkyl groups. Preferably, R2 may optionally be substituted by one or more substituents independently selected from methyl and trifluoromethyl.

[0033] In this embodiment, R3 may be selected from C 1-6 alkyl, halogenated C 1-6 alkyl, halogen, and cyano. Preferably, R3 may be selected from C 1-6 alkyl, halogenated C 1-6 alkyl, and halogen. More preferably, R3 may be selected from C 1-3 alkyl, fluorinated C 1-3 alkyl, and halogen. Both W and X are C.

[0034] In this embodiment, Z may be -CH2-.

[0035] In this embodiment, Y may be -O-.

[0036] In a preferred embodiment, the compounds represented by general formula (I) may be selected from the following compounds:

[0037]

[0038]

[0039]

[0040]

[0041] The compounds described herein can be made and / or used as pharmaceutically acceptable salts. The above-mentioned pharmaceutically acceptable salts can be inorganic acid salts and organic acid salts. The above-mentioned inorganic acid salts can be salts formed with hydrohalic acids, nitric acid, carbonic acid, sulfuric acid, phosphoric acid, etc. The above-mentioned organic acid salts can be salts formed with malic acid, citric acid, fumaric acid, oxalic acid, lactic acid, camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, etc. The hydrohalic acid can be hydrofluoric acid, hydrobromic acid, hydroiodic acid or hydrochloric acid. The above-mentioned pharmaceutically acceptable salts can be prepared by methods well known to those skilled in the art.

[0042] In a second aspect, the present invention provides a method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof. The preparation method of the present invention can be achieved by one of the following routes.

[0043] Route 1: Condense the substituted 2,3-diamino aromatic ring compound of formula a with an aldehyde group to obtain the compound of formula b; subject the compound of formula b to a substitution reaction with a haloalkane to obtain the compound of formula c; subject the compound of formula c to a substitution reaction to obtain the compound of general formula (I).

[0044]

[0045] Route 1

[0046] Route 2: Subject the substituted 2-fluoro-1-nitro aromatic ring compound of formula a to a substitution reaction with a primary amine compound to obtain the compound of formula b'; react the compound of formula b' with an aromatic ring compound to obtain the compound of formula c'; reduce the compound of formula c' under hydrogen conditions to obtain the compound of formula d; condense the compound of formula d with a carboxylic acid and then close the ring to obtain the compound of general formula (I).

[0047]

[0048] Route 2

[0049] Route 3: Subject the substituted 2-fluoro-1-nitro aromatic ring compound of formula a" to a substitution reaction with a primary amine compound to obtain the compound of formula b"; reduce the compound of formula b" under hydrogen conditions to obtain the compound of formula c"; condense the compound of formula c" with a carboxylic acid and then close the ring to obtain the compound of formula d"; react the compound of formula d" with an aromatic ring compound to obtain the compound of general formula (I).

[0050]

[0051] Route 3

[0052] The present invention provides, in a third aspect, a pharmaceutical composition comprising a compound according to the first aspect of the present invention or a pharmaceutically acceptable excipient thereof.

[0053] The above-mentioned pharmaceutically acceptable excipients may be conventional diluents, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, flavoring agents, sweetening agents, etc. in the pharmaceutical field.

[0054] The pharmaceutical composition of the present invention can be formulated according to techniques known in the art. The pharmaceutical composition can be in any form suitable for oral, parenteral, topical, intranasal, intrapulmonary, sublingual, ophthalmic, otic, rectal, intravaginal or transdermal administration. In the present invention, the pharmaceutical composition is preferably in a form suitable for topical administration.

[0055] The present invention provides, in a fourth aspect, the use of a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof for the treatment of TRPV3-related skin diseases.

[0056] The present invention provides, in a fifth aspect, a method for treating TRPV3-related skin diseases, which comprises administering a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0057] The present invention provides, in a sixth aspect, the use of a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of TRPV3-related skin diseases.

[0058] The dosage form of the above-mentioned medicament can be in various forms such as tablets, capsules, patches, ointments, emulsions, suspensions, gels, powders, granules, oral liquids and injections, etc. Preferably, the dosage form of the medicament is a dosage form suitable for topical administration. These dosage forms can all be prepared according to conventional methods in the pharmaceutical field.

[0059] In the present invention, TRPV3-related skin diseases include but are not limited to chronic pruritus, acute pruritus, atopic dermatitis, psoriasis, eczema, neuropathic pain, Olmsted syndrome, hereditary palmoplantar keratoderma, etc. Description of the Drawings

[0060] Figure 1 Showing the number of scratching times within 30 minutes after administration in a carvacrol-induced mouse pruritus model;

[0061] Figure 2 Showing the statistical results of the total number of scratching times within 30 minutes after administration in a carvacrol-induced mouse pruritus model. *P<0.05, ****P<0.0001 compared with the normal control group; △ P<0.05, △△ P<0.01,△△△ P < 0.001 compared with the model group; # P < 0.05, ## P < 0.01, #### P < 0.0001 compared with the solvent control group. Detailed implementation manners

[0062] The present invention will be further described in conjunction with embodiments. The following embodiments are only for illustrating the present invention and do not limit the present invention in any way.

[0063] The abbreviations used in the following synthesis steps are explained as follows:

[0064] DMF N,N-Dimethylformamide <![CDATA[K2CO3]]> Potassium carbonate PE Petroleum ether EA Ethyl acetate <![CDATA[H2O]]> Water THF Tetrahydrofuran DIPEA N,N-Diisopropylethylamine DEAD Diethyl azodicarboxylate DCM Dichloromethane TFA Trifluoroacetic acid NaOH Sodium hydroxide t-BuONa Sodium tert-butoxide BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl <![CDATA[Pd2(dba)3]]> Tris(dibenzylideneacetone)dipalladium(0) EtOH Ethanol Con.HCl Concentrated hydrochloric acid HATU 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate DCE Dichloroethane ACE Acetone KI Potassium iodide ACN Acetonitrile

[0065] Preparation Example 1. Synthesis of Compounds 1-7

[0066]

[0067]

[0068] Step 1. Synthesis of Intermediates 1c-7c

[0069] Add compound 1a (1 g, 5.4 mmol) dissolved in DMF (10 mL) into a 50 mL three-necked flask respectively. Add compounds 1b-5b (10.8 mmol) and K2CO3 (16.2 mmol) respectively, and heat to 100 °C for reaction for 16 hours. After the reaction is completed, cool to room temperature, dilute with water, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate to obtain the crude product, and purify with a chromatography column (PE:EA = 10:1) to obtain compounds 1c-5c respectively, and the yields are 88%, 88%, 88%, 88% and 86% respectively.

[0070] Add compound 1a (1 g, 5.4 mmol) dissolved in H2O (10 mL) into a 50 mL three-necked flask. Add compound 6b (8.1 mmol) and K2CO3 (27 mmol), and heat to 40 °C for reaction for 16 hours. After the reaction is completed, cool to room temperature, dilute with water, adjust the pH to 1 with 1N hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to obtain compound 6c, with a yield of 91%.

[0071] In a 50 mL three-necked flask, add compound 1a (1 g, 5.4 mmol) dissolved in THF (10 mL), add compound 7b (6.5 mmol) and DIPEA (10.8 mmol), and heat to 60 °C for reaction for 16 hours. After the reaction is completed, cool to room temperature, dilute with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by column chromatography (PE:EA = 10:1) to obtain compound 7c with a yield of 46%.

[0072] Step 2. Synthesis of Compounds 1-7

[0073] Add compounds 1c-6c (4.3 mmol) dissolved in THF (10 mL) to a 50 mL three-necked flask respectively, add compounds 1d-6d (5.6 mmol) and triphenylphosphine (5.6 mmol), cool to 0 °C, and dropwise add DEAD (5.6 mmol), and react at 25 °C for 16 hours. After the reaction is completed, dilute with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by column chromatography (PE:EA = 30:1) to obtain compounds 1-6 with yields of 86%, 61%, 86%, 86%, 86% and 86% respectively.

[0074] Add compound 7c (0.8 g, 2.5 mmol) dissolved in DMF (10 mL) to a 50 mL three-necked flask, add p-cresol (0.5 g, 5.0 mmol) and K2CO3 (1.0 g, 7.5 mmol), and heat to 100 °C for reaction for 16 hours. After the reaction is completed, cool to room temperature, add water to dilute the reaction solution, extract once with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by column chromatography (PE:EA = 10:1) to obtain compound 7 with a yield of 57%.

[0075] The structures of the synthesized compounds 1-7 were confirmed by NMR and mass spectrometry characterization. The 1 1H NMR and MS (ESI) results are shown in the following table.

[0076]

[0077]

[0078] Preparation Example 2. Synthesis of Compounds 8-9

[0079]

[0080] Step 1. Synthesis of Intermediates 8b, 9b

[0081] In a 100 mL three-necked flask, add compound 8a, 9a (1.0 g, 6.9 mmol), hexafluoroacetylacetone (1.7 g, 8.3 mmol), iron(III) trifluoromethanesulfonate (0.4 g, 0.7 mmol) and DMF (10 mL), and heat to 80 °C for 16 hours. After the reaction, dilute with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by column chromatography (PE:EA = 5:1) to obtain compounds 8b, 9b with yields of 99% and 95% respectively. Step 2. Synthesis of intermediates 8c, 9c

[0082] Refer to Step 1 in Preparation Example 1 for the synthesis procedure.

[0083] Step 3. Synthesis of intermediates 8, 9

[0084] Refer to Step 2 in Preparation Example 1 for the synthesis procedure.

[0085] The structures of the synthesized compounds 8 - 9 were confirmed by NMR and mass spectrometry. The 1 1H NMR and MS (ESI) results of compounds 8 - 9 are shown in the following table.

[0086]

[0087] Preparation Example 3. Synthesis of compound 10

[0088]

[0089] Step 1. Synthesis of intermediate 10b

[0090] Refer to Step 1 in Preparation Example 1 for the synthesis procedure, and use N-Boc-bromoethylamine instead of 2-bromoethanol as the raw material to prepare compound 10b.

[0091] Step 2. Synthesis of intermediate 10c

[0092] Dissolve compound 10b (1.0 g, 5.4 mmol) in DCM (10 mL), add TFA (2 mL), and react at 25 °C for 16 hours. After the reaction, concentrate under reduced pressure, dilute with water, adjust the pH to 9 with NaOH (1N), extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain compound 10c with a yield of 93%.

[0093] Step 3. Synthesis of compound 10

[0094] Compound 10c (1.0 g, 4.4 mmol) was dissolved in toluene (10 mL). p-Bromotoluene (0.8 g, 4.4 mmol), sodium tert-butoxide (1.3 g, 13.2 mmol), BINAP (0.44 mmol), and Pd2(dba)3 (0.44 mmol) were added. After displacing nitrogen, the mixture was heated to 100 °C and reacted for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, purified by a chromatography column (PE:EA = 10:1), and the crude product was separated by a preparative silica gel plate (100% DCM) to obtain Compound 10 with a yield of 5%.

[0095] The structure of the synthesized Compound 10 was confirmed by NMR and mass spectrometry characterization. The 1 1H NMR and MS (ESI) results of Compound 10 are shown in the following table.

[0096]

[0097] Preparation Example 4. Synthesis of Compounds 11 - 15

[0098]

[0099] Step 1. Synthesis of Intermediate 11b

[0100] Compound 11a (4.0 g, 22.6 mmol), ethanolamine (1.5 g, 24.8 mmol), DIPEA (4.4 g, 33.9 mmol), and EtOH (40 mL) were added to a 100 mL three-necked flask, and the mixture was heated to 80 °C and reacted for 16 hours. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, purified by a chromatography column (PE:EA = 10:1), and Compound 11b was obtained with a yield of 83%.

[0101] Step 2. Synthesis of Intermediate 11c

[0102] The synthesis steps refer to Step 2 in Preparation Example 1.

[0103] Step 3. Synthesis of Intermediate 11d

[0104] In a 100 mL three-necked flask, add compound 11c (2.0 g, 6.5 mmol), stannous chloride (3.6 g, 19.6 mmol), Conc. HCl (6 mL) and EtOH (20 mL), and heat to 80 °C for reaction for 3 hours. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, dilute with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by column chromatography (PE:EA = 5:1) to obtain compound 11d with a yield of 72%.

[0105] Step 4. Synthesis of intermediate 11e

[0106] In a 100 mL three-necked flask, add compound 11d (1.3 g, 4.7 mmol), phenylacetic acid (0.8 g, 6.1 mmol), HATU (2.2 g, 7.1 mmol) and DMF (15 mL), and react at 25 °C for 16 hours. After the reaction is completed, dilute with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by column chromatography (PE:EA = 4:1) to obtain compound 11e with a yield of 70%.

[0107] Step 5. Synthesis of compound 11

[0108] In a 100 mL three-necked flask, add compound 11e (1.3 g, 3.3 mmol), Conc. HCl (5 mL), acetic acid (4 mL) and DCE (26 mL), and heat to 110 °C for reaction for 16 hours. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, dilute with water, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by column chromatography (PE:ACE = 1:1) to obtain compound 11 with a yield of 8%.

[0109] Step 6. Synthesis of compounds 12 - 15

[0110] For the synthesis steps, refer to steps 1 - 5 in Preparation Example 4, replace the raw material 1,2,4-trifluoro-5-nitrobenzene with 1,4-difluoro-2-nitrobenzene, and replace phenylacetic acid with cyclopentanecarboxylic acid, benzoic acid, benzothiazole-2-carboxylic acid, 5-cyanopyridine-2-carboxylic acid respectively.

[0111] The structures of the synthesized compounds 11 - 15 were confirmed by NMR and mass spectrometry. The 1 1H NMR and MS (ESI) results are shown in the following table.

[0112]

[0113] Preparation Example 5. Synthesis of compounds 16 - 30

[0114]

[0115] Step 1. Synthesis of Intermediate 16b

[0116] Add compound 16a (5.0 g, 46.3 mmol), N-(tert-butoxycarbonyl)ethanolamine (9.7 g, 60.2 mmol), triphenylphosphine (15.8 g, 60.2 mmol) and THF (50 mL) into a 250 mL three-necked flask. Cool the mixture to 0 °C, and then dropwise add DEAD (10.5 g, 60.2 mmol). React at 25 °C for 16 hours. After the reaction is completed, dilute with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by column chromatography (PE:EA = 5:1) to obtain compound 16b with a yield of 93%.

[0117] Step 2. Synthesis of Intermediate 16c

[0118] Dissolve compound 16b (11.0 g, 43.8 mmol) in DCM (110 mL), add TFA (15 mL), and react at 25 °C for 16 hours. After the reaction is completed, concentrate under reduced pressure, dilute with water, adjust the pH to 9 with NaOH (1N), extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain compound 16c with a yield of 93%.

[0119] Step 3. Synthesis of Intermediate 16e

[0120] Add compound 16d (5.0 g, 24.9 mmol), compound 16c (4.3 g, 28.7 mmol), DIPEA (4.8 g, 37.4 mmol) and EtOH (50 mL) into a 100 mL three-necked flask. Heat the mixture to 80 °C and react for 16 hours. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, dilute with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by column chromatography (PE:DCM = 2:1) to obtain compound 16e with a yield of 91%.

[0121] Step 4. Synthesis of Intermediate 16f

[0122] Dissolve compound 16e (7.7 g, 22.6 mmol) in methanol (70 mL), add palladium on carbon (0.7 g, 10%), and react at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction is completed, filter off the palladium carbon, concentrate under reduced pressure to obtain compound 16f with a yield of 87%.

[0123] Step 5. Synthesis of Compound 16

[0124] Dissolve compound 16f (6.1 g, 19.6 mmol) in TFA (50 mL), and react at 80 °C for 16 hours. After the reaction is completed, concentrate under reduced pressure, dilute with water, adjust the pH to 9 with NaOH (1N), extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, purify by column chromatography (PE:EA = 20:1), slurry the concentrated residue with 50 mL of PE for 16 hours, filter, and dry the filter cake to obtain compound 16 with a yield of 67%.

[0125] Step 6. Synthesis of compounds 17 - 30

[0126] Refer to steps 1 - 5 of Preparation Example 5 for the synthesis steps, and replace starting materials 16a and 16d with the corresponding starting materials shown in the following table.

[0127]

[0128]

[0129] Step 7. Synthesis of intermediate 21d

[0130] Add 4 - fluoro - 3 - nitrophenol (1.0 g, 6.4 mmol), benzyl bromide (1.2 g, 7.0 mmol), K2CO3 (2.0 g, 14.5 mmol), KI (1.1 g, 6.4 mmol) and ACN (10 mL) to a 50 mL three - necked flask, and react at 25 °C for 16 h. Filter, rotary evaporate the filtrate to obtain the crude product. Purify by column chromatography (PE:EA = 10:1) to obtain intermediate 21d with a yield of 95%.

[0131] The structures of the synthesized compounds 16 - 30 were confirmed by NMR and mass spectrometry. The 1 1H NMR and MS (ESI) results are shown in the following table.

[0132]

[0133]

[0134]

[0135] Preparation Example 6. Synthesis of compounds 31 - 35

[0136]

[0137] Step 1. Synthesis of intermediate 31b

[0138] Compound 31a (15.7 g, 146.4 mmol) was dissolved in toluene (200 mL), 2-bromoethylamine hydrobromide (10.0 g, 48.8 mmol) was added, and the reaction was carried out at 120 °C for 4 hours. After the reaction was completed, it was cooled to room temperature, a large amount of solid precipitated, filtered, and the filter cake was washed twice with DCM (50 mL) and dried to obtain compound 31b with a yield of 89%.

[0139] Step 2. Synthesis of Compounds 31 - 35

[0140] For the synthesis steps, refer to Steps 3 - 5 in Preparation Example 5, where starting material 16c was replaced with 31b, and 16d was replaced with 31c - 35c respectively.

[0141] The structures of the synthesized compounds 31 - 35 were confirmed by NMR and mass spectrometry characterization. The 1 1H NMR and MS (ESI) results of compounds 31 - 35 are shown in the following table.

[0142]

[0143]

[0144] Test Example 1. In Vivo Inhibitory Activity Evaluation Experiment

[0145] Methods and Materials

[0146] Human embryonic kidney cells HEK-293 (obtained from the Cell Bank of the Chinese Academy of Sciences) were cultured in Dulbecco's Modified Eagle's medium (DMEM, obtained from Gibco), supplemented with 10% fetal bovine serum (FBS, obtained from PAM), in an incubator at 37°C with 95% air and 5% carbon dioxide. Human TRPV3 (hTRPV3) plasmid was transfected into HEK-293 cells using calcium phosphate transfection solution, which consisted of two types of solutions: Solution A containing 250 mM CaCl2 in pure water, and Solution B containing 1.5 mM Na2HPO4, 140 mM NaCl, and 50 mM HEPES (pH adjusted to 6.96). All electrophysiology recordings were performed at room temperature 24 hours after transfection using an Axon 200B, with the holding potential maintained at -60 mV. When filling the intracellular solution containing 140 mM CsCl, 10 mM HEPES, and 5 mM EGTA (pH adjusted to 7.4 using CsOH), the resistance of the patch electrode ranged from 3 to 5 MΩ. The cells were immersed in a standard extracellular solution containing 150 mM NaCl, 5 mM KCl, 10 mM glucose, 2 mM CaCl2, 1 mM MgCl2, and 10 mM HEPES (pH adjusted to 7.4 using Tris-base). The TRPV3 agonist 2-APB (3 mM), TRPV1 agonist capsaicin (1 μM), TRPV4 agonist GSK1016790A (100 nM), and all antagonists were diluted in an extracellular solution containing 150 mM NaCl, 5 mM KCl, 10 mM glucose, and 10 mM HEPES (pH adjusted to 7.4 using Tris-base) to prevent channel desensitization caused by Ca 2+ in the extracellular solution dilution. 2+ The data were sampled at 10 kHz and filtered at 2 kHz. The channels were repeatedly stimulated with agonists to ensure complete sensitization. All antagonists were pre-applied for 1 minute and then co-applied in the presence of agonists. Additionally, the TRPA1 agonist AITC (10 μM) and its antagonist (0.01 - 100 μM, approximately 3-fold dilution) were diluted in an agonist solution containing 150 mM NaCl, 5 mM KCl, 1 mM MgCl2, 10 mM glucose, and 10 mM HEPES (pH adjusted to 7.4 with Tris-base). The TRPA1 was first stimulated to open with the agonist, and then co-applied in the presence of the agonist. The raw data were analyzed using Origin software to obtain curves, and the IC 50 values were calculated using the Hill equation.

[0147] Experimental results

[0148] The typical compounds of the present invention were tested using the above methods and materials, and the IC 50 values (nM) of each compound inhibiting TRPA3 were obtained, and the results are shown in Table 1 below.

[0149] Table 1. In vitro activity data of the test compounds against human TRPV3

[0150] Compound Target channel <![CDATA[IC 50 (nM)]]> Compound 8 hTRPV3 1100 Compound 9 hTRPV3 100 Compound 16 hTRPV3 51 Compound 17 hTRPV3 2440 Compound 18 hTRPV3 66 Compound 22 hTRPV3 220 Compound 25 hTRPV3 85 Compound 30 hTRPV3 98

[0151] As can be seen from the above results, the compounds of the present invention can effectively inhibit TRPV3, and the IC 50 value (nM) reaches below 1000 nM, preferably below 500 nM, and more preferably below 100 nM under the above test conditions. Therefore, the compounds of the present invention can be used to treat TRPV3-related skin diseases, such as skin diseases caused by overexpression of TRPV3, such as pruritus and inflammation.

[0152] Using the above methods and materials, the IC 50 values (nM) of the typical compounds of the present invention inhibiting mTRPV3 (mouse TRPV3) and other TRP channels hTRPV1, mTRPV4 and hTRPA1 were also measured under the same conditions, and the results are shown together in Table 2 below.

[0153] Table 2. In vitro selectivity data of the test compounds

[0154]

[0155] As can be seen from the above results, the inhibitory activity of the compounds of the present invention against TRPV3 can be more than several tens of times stronger than that against TRPV1, TRPV4 and TRPA1. This indicates that the compounds of the present invention have high selectivity for TRPV3 and can be used as a specific and highly efficient TRPV3 inhibitor.

[0156] Thus, the compounds of the present invention can effectively act against the overexpression of TRPV3 without affecting the expression of other TRPs. It is particularly noteworthy that when using the compounds of the present invention to treat TRPV3-related skin diseases, such as skin diseases caused by overexpression of TRPV3, such as pruritus and inflammation, they can specifically act against the overexpression of TRPV3 without affecting the expression of other TRPs, thereby avoiding side effects on the nervous system, brain and other tissues.

[0157] Test Example 2. Pruritus pharmacodynamics experiment

[0158] Methods and materials

[0159] Carvacrol, as a skin sensitizer, has been shown to cause itching in mice by activating the TRPV3 channel. Liu et al. found that carvacrol-induced itching in mice was concentration-dependent, and no obvious itching was observed in mice with TRPV3 channel gene knockout. Therefore, the carvacrol-induced mouse itching model can be used to evaluate the targeting of compounds to inhibit TRPV3 and their pharmacological effects against itching.

[0160] Sixty-four SPF-grade C57BL / 6 mice (male, 6 - 8 weeks old) were used as experimental animals. After adaptive feeding, they were randomly divided into 8 groups: normal control group, model group, vehicle control group, positive control group, compound 18 (2% concentration) group, compound 18 (8% concentration) group, compound 25 (2% concentration) group, and compound 25 (8% concentration) group, with 8 mice in each group. Two days before the experiment, the hair on the back of the neck of the animals in an area of 2 * 3 cm 2 was removed. Thirty minutes before modeling, the corresponding test substances or vehicles were applied to the depilated area on the back of the neck according to the corresponding groups, 50 μl for each animal. Thirty minutes after the administration of the test substances, all animals except the blank control group were given an intradermal injection of 2% carvacrol on the back of the neck, with an injection dose of 50 μl / animal. For the prepared acute itching model, the itching indicators were that the mice scratched their heads with their front paws, scratched their trunks with their hind paws, and bit various parts of their bodies. A continuous scratching of the modeling area by the hind paws of the mice was recorded as one scratching. During the scratching process, if the animal paused, licked its paw, or put down its hind paw, and then scratched again, it was recorded as the second time. The number of scratchings during the observation period was observed and recorded. Among them, 5 minutes was used as a time unit to count the number of scratchings at each time point, and the total number of scratchings within 30 minutes was summarized. The number of scratchings within 30 minutes recorded and statistically analyzed for each group after drug administration was as Figure 1 shown.

[0161] The original data was analyzed using GraphPad software and statistically analyzed by one-way ANOVA. The results were as Figure 2 shown. *P < 0.05, ****P < 0.0001 compared with the normal control group; △ P < 0.05, △△ P < 0.01, △△△ P < 0.001 compared with the model group; # P < 0.05, ## P < 0.01, #### P < 0.0001 compared with the vehicle control group.

[0162] As can be seen from the above results, the mice in the model group (88.00±13.35) and the vehicle control group (74.25±13.76) showed obvious itching, with significant statistical differences compared with the normal control group (0.75±0.41) (P<0.0001), indicating successful modeling. The positive control compound dexamethasone acetate cream (20.63±3.84) could significantly improve the itching behavior, with significant differences compared with the model control group (P<0.001). Both 2% and 8% concentrations of compound 18 could reduce the itching times of mice, which were reduced to 34.75±14.71 and 42.75±11.42 respectively. Among them, compound 18 at 2% concentration had significant differences compared with the vehicle control group (74.25±13.76) (P<0.05). Both 2% and 8% concentrations of compound 25 significantly reduced the itching times of mice, which were reduced to 13.00±6.11 and 9.25±2.80 respectively, and both had significant differences compared with the vehicle control group (74.25±13.76) (P<0.0001). Moreover, the itching times of mice in the compound 25 group were lower than those in the positive control compound dexamethasone acetate cream group. The results showed that compound 18 and compound 25 could significantly improve the itching induced by carvacrol in mice. Among them, compound 25 had a tendency to be superior to dexamethasone in improving itching and showed a certain concentration dependence.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from hydrogen, hydroxyl, -C(=O)-NR’2, -S(=O)2-R’, -S(=O)2-NR’2, C1-C6 alkyl, halo C 1-6 alkyl, C1-C6 alkoxy, phenyl, benzyl, 5- or 6-membered heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, and C9-C 10 fused bicyclic heteroaryl, where R’ is independently H or C1-C3 alkyl, and the 5- or 6-membered heteroaryl, C3-C7 heterocycloalkyl, and C9-C 10 fused bicyclic heteroaryl contains 1 or 2 heteroatoms independently selected from N, O, and S and is optionally oxo, and R1 is optionally substituted with one or more groups independently selected from hydroxyl, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkylamino, di-C1-C3 alkylamino, acetylamino, N-methyl-N-acetylamino, and 5- or 6-membered cyclic amino; R2 is selected from phenyl, 5- or 6-membered heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, wherein the 5- or 6-membered heteroaryl and C3-C7 heterocycloalkyl contain 1 or 2 heteroatoms independently selected from N, O and S and are optionally oxo, and R2 is optionally substituted by one or more substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkylamino, di-C1-C3 alkylamino, acetylamino, N-methyl-N-acetylamino or 5- or 6-membered cyclic amino; R3 is selected from hydrogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen, cyano, nitro, amino, -S(=O)2-R' and -S(=O)2-NR'2, where R' is independently H or C1-C3 alkyl; W and X are each independently selected from N and C; Z is selected from -CH2-, -CH2-CH2- and -C(=O)-, and Z is optionally substituted by one or more groups independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkylamino, di-C1-C3 alkylamino, acetylamino, N-methyl-N-acetylamino or 5- or 6-membered cyclic amino; and Y is selected from -O-, -S-, -NH- and -N(C1-C3 alkyl)-.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R1 is selected from hydrogen, hydroxy, -S(=O)2-R', -S(=O)2-NR'2, phenyl, benzyl, pyridyl, benzothiazolyl, C 1-3 alkyl, C 3-7 cycloalkyl, halo C 1-3 alkyl and C 1-3 alkoxy, where R' is independently H or C1-C3 alkyl, and R1 is optionally substituted by one or more substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkylamino; R2 is selected from phenyl and 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl contains 1 or 2 heteroatoms independently selected from N, O, and S and is optionally oxo, and R2 is optionally substituted by one or more substituents independently selected from hydroxy, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkylamino; preferably, R2 is selected from phenyl and 5- to 6-membered heteroaryl containing 1-2 heteroatoms selected from O, N, and S, and R2 is optionally substituted by 1-3 substituents independently selected from halogen, cyano, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy; R3 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, -S(=O)2-R', -S(=O)2-NR'2, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy, wherein R' is independently H or C1-C3 alkyl; W and X are each independently selected from N and C; Z is selected from -CH2-, -CH2-CH2-, -C(=O)- and -CH(OH)CH2-; and Y is selected from -O-, -S- and -NH-.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R1 is selected from hydrogen, C1-C6 alkyl, halo C1-C6 alkyl, phenyl, benzyl, 5-6 membered heteroaryl, C3-C7 cycloalkyl and C9-C 10 fused bicyclic heteroaryl, the 5-6 membered heteroaryl, C3-C7 heterocycloalkyl and C9-C 10 fused bicyclic heteroaryl contains 1 or 2 heteroatoms independently selected from N, O and S, and R1 is optionally substituted by one or more groups independently selected from hydroxy, halogen, amino, cyano, nitro; preferably, R1 is selected from halo C1-C6 alkyl, phenyl, benzyl, 5-6 membered heteroaryl, C3-C7 cycloalkyl and C9-C 10 fused bicyclic heteroaryl, the 5-6 membered heteroaryl, C3-C7 heterocycloalkyl and C9-C 10 fused bicyclic heteroaryl contains 1 or 2 heteroatoms independently selected from N, O and S, and R1 is optionally substituted by cyano; more preferably, R1 is selected from trifluoromethyl, phenyl, benzyl, pyridyl, cyclopentyl and benzothiazolyl, and R1 is optionally substituted by cyano; R2 is selected from phenyl and 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, and R2 is optionally substituted by one or more substituents independently selected from hydroxy, halogen, amino, C1-C3 alkylamino, di-C1-C3 alkylamino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl and ; preferably, R2 is selected from phenyl, pyridyl and pyrimidinyl, and R2 is optionally substituted by one or more substituents independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl; R3 is selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen, cyano, nitro, amino, -S(=O)2-R' and -S(=O)2-NR'2, wherein R' is independently H or C1-C3 alkyl; preferably, R3 is selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen, cyano, -S(=O)2-C1-C3 alkyl and -S(=O)2-NH2; W and X are each independently selected from N and C; Z is selected from -CH2-, -CH2-CH2- and -C(=O)-, and Z is optionally substituted by one or more hydroxy groups; preferably, Z is selected from -CH2-, -CH2-CH2-, -CH(OH)-CH2- and -C(=O)-; Y is selected from -O-, -S- and -NH-; preferably, Y is selected from -O- and -NH-.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R1 is halo C1-C6 alkyl; preferably, R1 is trifluoromethyl; R2 is selected from phenyl and pyridyl, and R2 is optionally substituted by one or more substituents independently selected from C1-C3 alkyl and halo C1-C3 alkyl; R3 is selected from C 1-6 alkyl, halo C 1-6 alkyl, halogen, and cyano; preferably, R3 is selected from C 1-6 alkyl, halo C 1-6 alkyl, and halogen; Both W and X are C; Z is -CH2-; Y is -O-.

5. The compound or its pharmaceutically acceptable salt according to claim 1, wherein the compound is selected from: 1-(2-(p-Tolyloxy)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole, 1-(2-(p-Chlorophenoxy)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole, 4-(2-(2-(Trifluoromethyl)-1H-benzo[d]imidazol-1-yl)ethoxy)benzonitrile, 1-(2-(o-Methoxyphenoxy)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole, 1-(3-(p-Tolyloxy)propyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole, p-Tolyl 2-(2-(Trifluoromethyl)-1H-benzo[d]imidazolyl)acetate, 1-(p-Tolyloxy)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazolyl)2-propanol, 5,6-Difluoro-1-(2-(p-Tolyloxy)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole, 5,6-Dichloro-1-(2-(p-Tolyloxy)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole, 4-Methyl-N-(2-(2-(Trifluoromethyl)-1H-benzo[d]imidazol-1-yl)ethyl)aniline, 2-(Benzyl)-5,6-difluoro-1-(2-(p-Tolyloxy)ethyl)-1H-benzo[d]imidazole, 2-Cyclopentyl-5,6-difluoro-1-(2-(p-Tolyloxy)ethyl)-1H-benzo[d]imidazole, 2-(Phenyl)-5-fluoro-1-(2-(p-Tolyloxy)ethyl)-1H-benzo[d]imidazole, 2-(5,6-Difluoro-1-(2-(p-Tolyloxy)ethyl)-1H-benzo[d]imidazol-2-yl)benzothiazole, 6-(5-Fluoro-1-(2-(p-Tolyloxy)ethyl)-1H-benzo[d]imidazol-2-yl)nicotinonitrile, 1-(2-(p-Tolyloxy)ethyl)-2,5-bis-(trifluoromethyl)-1H-benzo[d]imidazole, 5-Fluoro-1-(2-(p-Tolyloxy)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole, 1-(2-((5-Methylpyridin-2-yl)oxy)ethyl)-2,5-bis(trifluoromethyl)-1H-benzo[d]imidazole, 6-Chloro-3-(2-(p-Tolyloxy)ethyl)-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine, 6-Fluoro-3-(2-(p-Tolyloxy)ethyl)-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine, 1-(2-(p-Tolyloxy)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-ol, 1-(2-(p-Tolyloxy)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-carbonitrile, 1-(2-(p-Tolyloxy)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-sulfonamide, 5-(Methylsulfonyl)-1-(2-(p-tolyloxy)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole, 5-Chloro-1-(2-(p-tolyloxy)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole, 5-Methyl-2-(trifluoromethyl)-1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)ethyl)-1H-benzo[d]imidazole, 1-(2-((2-Methylpyrimidin-5-yl)oxy)ethyl)-2,5-bis(trifluoromethyl)-1H-benzo[d]imidazole, 1-(2-((6-Methylpyridin-3-yl)oxy)ethyl)-2,5-bis(trifluoromethyl)-1H-benzo[d]imidazole, 1-(2-(Pyridin-4-yloxy)ethyl)-2,5-bis(trifluoromethyl)-1H-benzo[d]imidazole, 5-Methyl-2-(trifluoromethyl)-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-benzo[d]imidazole, N-(2-(5-Fluoro-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)ethyl)-4-methylaniline, N-(2-(5,6-Difluoro-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)ethyl)-4-methylaniline, N-(2-(5,6-Dichloro-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)ethyl)-4-methylaniline, N-(2-(2,5-Bis(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)ethyl)-4-methylaniline, and N-(2-(5-Chloro-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)ethyl)-4-methylaniline.

6. A method for preparing the compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof, characterized in that: The method comprises the following steps: Route 1: Condensing a substituted 2,3-diamino aromatic ring compound represented by formula a to obtain a compound represented by formula b; subjecting the compound represented by formula b to a substitution reaction with a haloalkane to obtain a compound represented by formula c; subjecting the compound represented by formula c to a substitution reaction to obtain a compound represented by general formula (I), Route 1 Alternatively, the method comprises the following steps: Route 2: Subjecting a substituted 2-fluoro-1-nitro aromatic ring compound represented by formula a to a substitution reaction with a primary amine compound to obtain a compound represented by formula b'; reacting the compound represented by formula b' with an aromatic ring compound to obtain a compound represented by formula c'; reducing the compound represented by formula c' under hydrogen conditions to obtain a compound represented by formula d; condensing the compound represented by formula d with a carboxylic acid and then cyclizing to obtain a compound represented by general formula (I), Route 2 Alternatively, the method comprises the following steps: Route 3: The substituted 2-fluoro-1-nitroaromatic ring compound shown in formula a" undergoes a substitution reaction with a primary amine compound to obtain the compound shown in formula b"; the compound shown in formula b" is reduced under hydrogen conditions to obtain the compound shown in formula c"; the compound shown in formula c" is condensed with a carboxylic acid and then cyclized to obtain the compound shown in formula d"; the compound shown in formula d" is reacted with an aromatic ring compound to obtain the compound shown in general formula (I). Route 3.

7. A pharmaceutical composition comprising the compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

8. Use of the compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof for the treatment of TRPV3-related skin diseases, said skin diseases being preferably selected from chronic pruritus, acute pruritus, atopic dermatitis, psoriasis, eczema, neuropathic pain, Olmsted syndrome, and hereditary palmoplantar keratoderma.

9. A method for treating TRPV3-related skin diseases, comprising administering an effective amount of the compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof to a subject in need thereof, said skin diseases being preferably selected from chronic pruritus, acute pruritus, atopic dermatitis, psoriasis, eczema, neuropathic pain, Olmsted syndrome, and hereditary palmoplantar keratoderma.

10. Use of the compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of TRPV3-related skin diseases, said skin diseases being preferably selected from chronic pruritus, acute pruritus, atopic dermatitis, psoriasis, eczema, neuropathic pain, Olmsted syndrome, and hereditary palmoplantar keratoderma.

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