TRPV3 inhibitor, and preparation therefor and use thereof

Abstract

Provided in the present invention are a compound as shown in general formula (I) as a TRPV3 inhibitor or a pharmaceutically acceptable salt thereof and a preparation method therefor. The compound or the pharmaceutically acceptable salt thereof can be used for treating or preventing TRPV3-related skin diseases. Further provided in the present invention are a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof, and the use of the compound or the pharmaceutically acceptable salt thereof in the treatment of TRPV3-related skin diseases.

Description

TRPV3 inhibitors and their preparation and use Technical Field

[0001] The present invention relates to TRPV3 inhibitor compounds, methods for their preparation, pharmaceutical compositions comprising such compounds, and uses of such compounds in the treatment of diseases. Specifically, the present invention relates to aromatic cyclic imidazole derivatives useful as TRPV3 inhibitors, methods for their preparation, pharmaceutical compositions comprising such derivatives, and uses of aromatic cyclic imidazole derivatives in the treatment of TRPV3-related skin diseases. Background Art

[0002] Transient receptor potential (TRP) channels, a family of non-selective cation channels, were first discovered in Drosophila photoreceptors by Cosen et al. in 1969. Mammalian TRP channels comprise 28 members, divided into seven subgroups based on 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 a variety of mechanisms and are involved in nearly all sensory modalities.

[0003] The TRPV subfamily of transient receptor potentials consists of six members: TRPV1 to TRPV6. All six TRPV subfamily members have an ankyrin repeat domain at their N-termini. The 33 residues that make up each ankyrin repeat sequence generally serve as an important motif for subunit-subunit interactions. Among the six subfamily members, TRPV1, TRPV2, TRPV3, and TRPV4 are the most important for Ca 2+ TRPV5 and TRPV6 are temperature-sensitive channels with suitable permeability for Ca 2+ Highly selective channel. 2+ TRPV3 is a temperature-sensitive channel with moderate permeability. It 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 cytoplasmic amino and carboxyl termini, ankyrin repeats, an amino-terminal helix-helix domain, six transmembrane segments, a reentrant pore loop, and numerous potential phosphorylation sites. Compared to the ankyrin repeat domains of TRPV1 and TRPV4, TRPV3 is thought to have six ankyrin repeats, an insertion in repeat 1, and two transient deletions in repeats 4 and 5. Furthermore, TRPV3 possesses a unique curved finger 3 loop that is maintained by hydrogen bonds and hydrophobic packing.

[0005] TRPV3 is expressed most abundantly in human and mouse skin keratinocytes and oral and nasal epithelia, but is also expressed in a variety of cells, including the brain, spinal cord, DRG, TG, and testes. TRPV1 is expressed in sensory neurons. More specifically, TRPV1 is expressed in approximately half of all somatic and visceral sensory neurons, with expression restricted to small to medium-sized neurons in the dorsal root ganglion, trigeminal ganglion, and vagal ganglion. TRPV1 is also expressed in perivascular sensory neurons, regulating vasodilation. TRPV1 expression in arteriolar smooth muscle may control blood flow to 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. Furthermore, TRPV2 is expressed in multiple regions of the brain. TRPV4 is widely expressed in numerous tissues.

[0006] Compared to TRPV1, the most studied member of the TRPV family, TRPV3 has been slow to develop due to a lack of effective and selective agonists or inhibitors. The analysis of the TRPV3 cryo-electron microscopy structure provided new opportunities for TRPV3 research. However, most initial TRPV3 inhibitors were natural products, requiring high effective doses and potentially causing serious side effects. Subsequently, Glenmark Pharmaceuticals, Hydra Biosciences, and Abbvie Inc. began developing small molecule TRPV3 inhibitors, but existing TRPV3 inhibitors still suffer from insufficient efficacy and poor selectivity.

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

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

[0009] in:

[0010] R1 can be selected from hydrogen, hydroxy, -C(=O)-NR'2, -S(=O)2-R', -S(=O)2-NR'2, C1-C6 alkyl, halogenated C 1-6 Alkyl, C1-C6 alkoxy, phenyl, benzyl, 5-6 membered heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocyclyl and C9-C 10Fused bicyclic heteroaryl, wherein R' is independently H or C1-C3 alkyl, the 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 be optionally oxo-substituted, and R1 may be 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, diC1-C3 alkylamino, acetylamino, N-methyl-N-acetylamino and 5-6 membered cyclic amino;

[0011] R2 may be selected from phenyl, 5-6 membered heteroaryl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, wherein the 5-6 membered heteroaryl and C3-C7 heterocyclyl may contain 1 or 2 heteroatoms independently selected from N, O and S and may be optionally oxo-substituted, and R2 may be optionally substituted with 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, diC1-C3 alkylamino, acetylamino, N-methyl-N-acetylamino or 5-6 membered cyclic amino;

[0012] R3 can be 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;

[0013] W and X are each independently selected from N and C;

[0014] Z may be selected from -CH2-, -CH2-CH2- and -C(=O)-, and may be 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 a 5-6 membered cyclic amino group; and

[0015] Y may be selected from -O-, -S-, -NH- and -N(C1-C3 alkyl)-.

[0016] In one embodiment, in the general formula (I), R1 can be selected from hydrogen, hydroxyl, -S(=O)2-R', -S(=O)2-NR'2, phenyl, benzyl, pyridyl, benzothiazolyl, C 1-3Alkyl, C 3-7 Cycloalkyl, halogenated C 1-3 Alkyl and C 1-3 Alkoxy, wherein R' is independently H or C1-C3 alkyl, and R1 may be optionally substituted with 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.

[0017] In this embodiment, R2 can be selected from phenyl and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl can contain 1 or 2 heteroatoms independently selected from N, O and S and is optionally oxo-substituted, and R2 can be optionally substituted by one or more substituents independently selected from hydroxyl, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkylamino.

[0018] Preferably, R2 can be selected from phenyl and 5-6 membered aromatic hetero groups containing 1-2 heteroatoms selected from O, N and S, and R2 can be optionally substituted by 1-3 groups independently selected from halogen, cyano, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 substituted by an alkoxy substituent.

[0019] In this embodiment, R3 can be selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, -S(=O)2-R', -S(=O)2-NR'2, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, wherein R' is independently H or C1-C3 alkyl.

[0020] In this embodiment, W and X are each independently selected from N and C.

[0021] In this embodiment, Z may be selected from -CH2-, -CH2-CH2-, -C(=O)-, and -CH(OH)CH2-.

[0022] In this embodiment, Y may be selected from -O-, -S-, and -NH-.

[0023] In another embodiment, in the general formula (I), R1 can be selected from hydrogen, C1-C6 alkyl, halogenated 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 be optionally substituted with one or more groups independently selected from hydroxy, halogen, amino, cyano, nitro.

[0024] Preferably, R1 can be selected from halogenated 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 10 The fused bicyclic heteroaryl may contain 1 or 2 heteroatoms independently selected from N, O and S, and R1 may be optionally substituted with a cyano group. More preferably, R1 may be selected from trifluoromethyl, phenyl, benzyl, pyridyl, cyclopentyl and benzothiazolyl, and R1 may be optionally substituted with a cyano group. Further more preferably, R1 may be trifluoromethyl.

[0025] In this embodiment, R2 can be selected from phenyl and a 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, and R2 can be optionally substituted by one or more substituents independently selected from hydroxy, halogen, amino, C1-C3 alkylamino, diC1-C3 alkylamino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl and. Preferably, R2 can be selected from phenyl, pyridyl and pyrimidyl, and R2 can be optionally substituted by one or more substituents independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl. More preferably, R2 can be optionally substituted by one or more substituents independently selected from C1-C3 alkyl and halo-C1-C3 alkyl. Further more preferably, R2 can be optionally substituted by methyl or trifluoromethyl.

[0026] In this embodiment, R3 may be 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 can be selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 More preferably, R3 can be selected from C 1-6 Alkyl, halogenated C 1-6 More preferably, R3 can be selected from C 1-3 Alkyl, fluorinated C 1-3 Alkyl, halogen and cyano.

[0027] In this embodiment, W and X are each independently selected from N and C.

[0028] In this embodiment, Z can be selected from -CH2-, -CH2-CH2- and -C(=O)-, and Z can be optionally substituted with one or more hydroxyl groups. Preferably, Z can be selected from -CH2-, -CH2-CH2-, -CH(OH)-CH2- and -C(=O)-. More preferably, Z can be -CH2-.

[0029] 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-.

[0030] In yet another embodiment, in formula (I), R1 can be a halogenated C1-C6 alkyl group. Preferably, R1 can be a fluorinated C1-C3 alkyl group. More preferably, R1 can be a trifluoromethyl group.

[0031] In this embodiment, R2 can be selected from phenyl and pyridyl, and R2 can be optionally substituted by one or more substituents independently selected from C1-C3 alkyl and halo C1-C3 alkyl.Preferably, R2 can be optionally substituted by one or more substituents independently selected from methyl and trifluoromethyl.

[0032] In this embodiment, R3 can be selected from C 1-6 Alkyl, halogenated C 1-6 Preferably, R3 can be selected from C 1-6 Alkyl, halogenated C 1-6 More preferably, R3 can be selected from C 1-3 Alkyl, fluorinated C 1-3 Alkyl and halogen. W and X are both C.

[0033] In this embodiment, Z may be -CH2-.

[0034] In this embodiment, Y may be -O-.

[0035] In a preferred embodiment, the compound represented by general formula (I) can be selected from the following compounds:

[0036] The compounds described herein can be prepared and / or used as pharmaceutically acceptable salts. These pharmaceutically acceptable salts can be inorganic acid salts or organic acid salts. These inorganic acid salts can be salts formed with hydrohalic acids, nitric acid, carbonic acid, sulfuric acid, phosphoric acid, and the like. These 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, and the like. The hydrohalic acid can be hydrofluoric acid, hydrobromic acid, hydroiodic acid, or hydrochloric acid. These pharmaceutically acceptable salts can be prepared by methods well known to those skilled in the art.

[0037] In a second aspect, the present invention provides a method for preparing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. The preparation method of the present invention can be achieved by one of the following routes.

[0038] Route 1: Condensing a substituted 2,3-diamino aromatic compound of formula a with an aldehyde group to obtain a compound of formula b; subjecting the compound of formula b to a substitution reaction with a halogenated alkane to obtain a compound of formula c; subjecting the compound of formula c to a substitution reaction to obtain a compound of general formula (I).

[0039] Route 2: The substituted 2-fluoro-1-nitro aromatic compound of formula a is subjected to a substitution reaction with a primary amine compound to obtain a compound of formula b'; the compound of formula b' is reacted with an aromatic compound to obtain a compound of formula c'; the compound of formula c' is reduced under hydrogen conditions to obtain a compound of formula d; the compound of formula d is condensed with a carboxylic acid and then ring-closed to obtain a compound of general formula (I).

[0040] Route 3: A substituted 2-fluoro-1-nitro aromatic ring compound represented by formula a" is subjected to a substitution reaction with a primary amine compound to obtain a compound represented by formula b"; the compound represented by formula b" is reduced under hydrogen conditions to obtain a compound represented by formula c"; the compound represented by formula c" is condensed with a carboxylic acid and then ring-closed to obtain a compound represented by formula d"; the compound represented by formula d" is reacted with an aromatic ring compound to obtain a compound represented by general formula (I).

[0041] In a third aspect, the present invention provides a pharmaceutical composition comprising the compound according to the first aspect of the present invention or a pharmaceutically acceptable excipient thereof.

[0042] The pharmaceutically acceptable excipients mentioned above may be conventional diluents, fillers, binders, wetting agents, disintegrants, absorption accelerators, surfactants, adsorption carriers, lubricants, flavoring agents, sweeteners, etc. in the pharmaceutical field.

[0043] The pharmaceutical compositions of the present invention can be formulated according to techniques known in the art. The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ocular, otic, rectal, vaginal or transdermal administration. In the present invention, the pharmaceutical compositions are preferably in a form suitable for topical administration.

[0044] In a fourth aspect, the present invention provides use of the compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof for treating TRPV3-related skin diseases.

[0045] In a fifth aspect, the present invention provides a method for treating TRPV3-related skin diseases, comprising administering the compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0046] In a sixth aspect, the present invention provides use of the compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating TRPV3-related skin diseases.

[0047] The dosage form of the above-mentioned medicine can be various forms such as tablets, capsules, patches, ointments, emulsions, suspensions, gels, powders, granules, oral liquids and injections. Preferably, the dosage form of the medicine is a dosage form suitable for topical administration. These dosage forms can be prepared according to conventional methods in the pharmaceutical field.

[0048] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 shows the number of scratching within 30 minutes after administration in a carvacrol-induced itch model in mice;

[0050] Figure 2 shows the statistical results of the total number of scratching within 30 minutes after administration in the carvacrol-induced pruritus model in mice. *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. DETAILED DESCRIPTION

[0051] The present invention is further described with reference to the following examples. The following examples are only intended to illustrate the present invention and are not intended to limit the present invention in any way.

[0052] The abbreviations used in the following synthetic steps are as follows:

[0053] Preparation Example 1. Synthesis of Compound 1-7

[0054] Step 1. Synthesis of intermediates 1c-7c

[0055] In a 50 mL three-necked flask, compound 1a (1 g, 5.4 mmol) dissolved in DMF (10 mL) was added, followed by compounds 1b-5b (10.8 mmol) and K2CO3 (16.2 mmol). The mixture was heated to 100°C and reacted for 16 hours. After the reaction, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 10:1) to obtain compounds 1c-5c in yields of 88%, 88%, 88%, 88%, and 86%, respectively.

[0056] In a 50 mL three-necked flask, compound 1a (1 g, 5.4 mmol) was dissolved in H₂O (10 mL). Compound 6b (8.1 mmol) and K₂CO₃ (27 mmol) were then added. The mixture was heated to 40°C and reacted for 16 hours. After the reaction, the mixture was cooled to room temperature, diluted with water, and the pH was adjusted to 1 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound 6c in a 91% yield.

[0057] In a 50 mL three-necked flask, compound 1a (1 g, 5.4 mmol) was dissolved in THF (10 mL). Compound 7b (6.5 mmol) and DIPEA (10.8 mmol) were added and heated to 60°C for 16 hours. After the reaction, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The product was purified by column chromatography (PE:EA = 10:1) to obtain compound 7c in a 46% yield.

[0058] Step 2. Synthesis of Compound 1-7

[0059] In a 50 mL three-necked flask, compounds 1c-6c (4.3 mmol) dissolved in THF (10 mL) were added, followed by compounds 1d-6d (5.6 mmol) and triphenylphosphine (5.6 mmol). The temperature was cooled to 0°C, and DEAD (5.6 mmol) was added dropwise. The mixture was allowed to react at 25°C for 16 hours. After completion of the reaction, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 30:1) to afford compounds 1-6 in yields of 86%, 61%, 86%, 86%, 86%, and 86%, respectively.

[0060] Compound 7c (0.8 g, 2.5 mmol) was dissolved in DMF (10 mL) in a 50 mL three-necked flask. p-Cresol (0.5 g, 5.0 mmol) and K2CO3 (1.0 g, 7.5 mmol) were added and heated to 100°C for 16 hours. After the reaction, the mixture was cooled to room temperature and diluted with water. The mixture was extracted once with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The product was purified by column chromatography (PE:EA = 10:1) to obtain compound 7 in a 57% yield.

[0061] The structures of the synthesized compounds 1-7 were confirmed by NMR and mass spectrometry. 1 The results of H NMR and MS (ESI) are shown in the following table.

[0062] Preparation Example 2. Synthesis of Compound 8-9

[0063] Step 1. Synthesis of intermediates 8b, 9b

[0064] Compounds 8a and 9a (1.0 g, 6.9 mmol), hexafluoroacetylacetone (1.7 g, 8.3 mmol), iron trifluoromethanesulfonate (0.4 g, 0.7 mmol), and DMF (10 mL) were added to a 100 mL three-necked flask and heated to 80°C for 16 hours. After completion of the reaction, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 5:1) to afford compounds 8b and 9b in yields of 99% and 95%, respectively.

[0065] Step 2. Synthesis of intermediates 8c, 9c

[0066] The synthesis steps are similar to those in Step 1 of Preparation Example 1.

[0067] Step 3. Synthesis of intermediates 8, 9

[0068] The synthesis steps refer to Step 2 in Preparation Example 1.

[0069] The structures of the synthesized compounds 8-9 were confirmed by NMR and mass spectrometry. 1 The results of H NMR and MS (ESI) are shown in the following table.

[0070] Preparation Example 3. Synthesis of Compound 10

[0071] Step 1. Synthesis of Intermediate 10b

[0072] The synthesis steps were similar to those in Step 1 of Preparation Example 1, except that N-Boc-bromoethylamine was used as the starting material instead of 2-bromoethanol to prepare Compound 10b.

[0073] Step 2. Synthesis of Intermediate 10c

[0074] Compound 10b (1.0 g, 5.4 mmol) was dissolved in DCM (10 mL), and TFA (2 mL) was added. The mixture was reacted at 25°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 9 with NaOH (1N). The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford compound 10c in a 93% yield.

[0075] Step 3. Synthesis of compound 10

[0076] Compound 10c (1.0 g, 4.4 mmol) was dissolved in toluene (10 mL), and 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 nitrogen displacement, the mixture was heated to 100°C and reacted for 12 hours. After the reaction, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 10:1) and separated on a preparative silica gel plate (100% DCM) to obtain compound 10 in a 5% yield.

[0077] The structure of the synthesized compound 10 was confirmed by NMR and mass spectrometry. 1 The results of H NMR and MS (ESI) are shown in the following table.

[0078] Preparation Example 4. Synthesis of Compounds 11-15

[0079] Step 1. Synthesis of intermediate 11b

[0080] 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 heated to 80°C for 16 hours. After the reaction, the mixture 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, and concentrated to obtain a crude product, which was purified by column chromatography (PE:EA = 10:1) to obtain compound 11b in an 83% yield.

[0081] Step 2. Synthesis of intermediate 11c

[0082] The synthesis steps refer to Step 2 in Preparation Example 1.

[0083] Step 3. Synthesis of intermediate 11d

[0084] Compound 11c (2.0 g, 6.5 mmol), stannous chloride (3.6 g, 19.6 mmol), Con-HCl (6 mL), and EtOH (20 mL) were added to a 100 mL three-necked flask and heated to 80°C for 3 hours. After the reaction, the mixture 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, and concentrated to obtain a crude product, which was purified by column chromatography (PE:EA = 5:1) to obtain compound 11d in a yield of 72%.

[0085] Step 4. Synthesis of intermediate 11e

[0086] 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) were added to a 100 mL three-necked flask and reacted at 25°C for 16 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 4:1) to obtain compound 11e in a 70% yield.

[0087] Step 5. Synthesis of compound 11

[0088] Compound 11e (1.3 g, 3.3 mmol), Con-HCl (5 mL), acetic acid (4 mL), and DCE (26 mL) were added to a 100 mL three-necked flask and heated to 110°C for 16 hours. After the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure, diluted with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (PE:ACE = 1:1) to obtain compound 11 in an 8% yield.

[0089] Step 6. Synthesis of compounds 12-15

[0090] The synthesis steps were similar to steps 1-5 in Preparation Example 4, except that the raw material 1,2,4-trifluoro-5-nitrobenzene was replaced with 1,4-difluoro-2-nitrobenzene, and the phenylacetic acid was replaced with cyclopentanoic acid, benzoic acid, benzothiazole-2-carboxylic acid, and 5-cyanopyridine-2-carboxylic acid, respectively.

[0091] The structures of the synthesized compounds 11-15 were confirmed by NMR and mass spectrometry. 1 The results of H NMR and MS (ESI) are shown in the following table.

[0092] Preparation Example 5. Synthesis of Compounds 16-30

[0093] Step 1. Synthesis of intermediate 16b

[0094] Compound 16a (5.0 g, 46.3 mmol), N-(tert-butyloxycarbonyl)ethanolamine (9.7 g, 60.2 mmol), triphenylphosphine (15.8 g, 60.2 mmol), and THF (50 mL) were added to a 250 mL three-necked flask. The temperature was lowered to 0°C, and DEAD (10.5 g, 60.2 mmol) was added dropwise. The mixture was allowed to react at 25°C for 16 hours. After completion of the reaction, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by column chromatography (PE:EA = 5:1) to obtain compound 16b in a 93% yield.

[0095] Step 2. Synthesis of intermediate 16c

[0096] Compound 16b (11.0 g, 43.8 mmol) was dissolved in DCM (110 mL), and TFA (15 mL) was added. The mixture was reacted at 25°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 9 with NaOH (1N). The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford compound 16c in a 93% yield.

[0097] Step 3. Synthesis of intermediate 16e

[0098] 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) were added to a 100 mL three-necked flask and heated to 80°C for 16 hours. After the reaction, the mixture 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, and concentrated to obtain a crude product, which was purified by column chromatography (PE:DCM = 2:1) to obtain compound 16e in a 91% yield.

[0099] Step 4. Synthesis of Intermediate 16f

[0100] Compound 16e (7.7 g, 22.6 mmol) was dissolved in methanol (70 mL), and palladium on carbon (0.7 g, 10%) was added. The mixture was reacted at 25°C under a hydrogen atmosphere for 16 hours. After the reaction, the palladium on carbon was removed by filtration and the mixture was concentrated under reduced pressure to obtain compound 16f in an 87% yield.

[0101] Step 5. Synthesis of compound 16

[0102] Compound 16f (6.1 g, 19.6 mmol) was dissolved in TFA (50 mL) and reacted at 80°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 9 with NaOH (1N). The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 20:1). The concentrated residue was slurried with 50 mL of PE for 16 hours, filtered, and the filter cake was dried to obtain compound 16 in a yield of 67%.

[0103] Step 6. Synthesis of Compounds 17-30

[0104] The synthesis steps were similar to those in Steps 1 to 5 of Preparation Example 5, except that the raw materials 16a and 16d were replaced with the corresponding raw materials shown in the table below.

[0105] Step 7. Synthesis of Intermediate 21d

[0106] To a 50 mL three-necked flask, 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) were added and reacted at 25°C for 16 h. The mixture was filtered and the filtrate was dried to give the crude product. Purification by column chromatography (PE:EA = 10:1) afforded Intermediate 21d in a 95% yield.

[0107] The structures of the synthesized compounds 16-30 were confirmed by NMR and mass spectrometry. 1 The results of H NMR and MS (ESI) are shown in the following table.

[0108] Preparation Example 6. Synthesis of Compounds 31-35

[0109] Step 1. Synthesis of intermediate 31b

[0110] Compound 31a (15.7 g, 146.4 mmol) was dissolved in toluene (200 mL), and 2-bromoethylamine hydrobromide (10.0 g, 48.8 mmol) was added. The mixture was reacted at 120°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, whereupon a large amount of solid precipitated. The solid was filtered, and the filter cake was washed twice with DCM (50 mL) and dried to obtain compound 31b in an 89% yield.

[0111] Step 2. Synthesis of compounds 31-35

[0112] The synthesis steps were similar to steps 3-5 in Preparation Example 5, except that the raw material 16c was replaced by 31b, and 16d was replaced by 31c-35c, respectively.

[0113] The structures of the synthesized compounds 31-35 were confirmed by NMR and mass spectrometry. 1 The results of H NMR and MS (ESI) are shown in the following table.

[0114] Test Example 1. In vivo inhibitory activity evaluation experiment

[0115] Methods and Materials

[0116] Human embryonic kidney (HEK)-293 cells (obtained from the Cell Bank of the Chinese Academy of Sciences) were cultured in Dulbecco's Modified Eagle's Medium (DMEM, Gibco) supplemented with 10% fetal bovine serum (FBS, PAM) at 37°C in an incubator with 95% air and 5% carbon dioxide. Human TRPV3 (hTRPV3) plasmids were transfected into HEK-293 cells using a calcium phosphate transfection solution consisting of two 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 (adjusted to pH 6.96). All electrophysiological recordings were performed 24 hours after transfection at room temperature using an Axon 200B microscope, with a holding potential of -60 mV. When filled with an 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 MQ. 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), the TRPV1 agonist capsaicin (1 μM), the TRPV4 agonist GSK1016790A (100 nM), and all antagonists were added to the standard extracellular solution containing 150 mM NaCl, 5 mM KCl, 10 mM glucose, and 10 mM HEPES (pH adjusted to 7.4 using Tris-base). 2+ Extracellular solution is diluted to prevent Ca 2+ Channel desensitization caused by agonists. Data were sampled at 10kHz and filtered at 2kHz. The channels were repeatedly stimulated with agonists to ensure that the channels were fully sensitized. All antagonists were pre-applied for 1 minute and then co-applied in the presence of agonists. In addition, the TRPA1 agonist AITC (10μM) and its antagonists (0.01-100μM, approximately 3-fold dilution) were diluted with an agonist containing 150mM NaCl, 5mM KCl, 1mM MgCl2, 10mM glucose, and 10mM HEPES (pH adjusted to 7.4 with Tris-base), first stimulated to open TRPA1 with agonists, and then co-applied in the presence of agonists. The raw data were analyzed with Origin software to obtain the curve, and the Hill formula was used to calculate the IC 50 value.

[0117] Experimental results

[0118] The typical compounds of the present invention were tested using the above methods and materials to obtain the IC values ​​of each compound for inhibiting TRPV3. 50 The results are shown in Table 1 below.

[0119] Table 1. In vitro activity data of the test compounds against human TRPV3

[0120] From the above results, it can be seen that the compounds of the present invention can effectively inhibit TRPV3. Under the above test conditions, IC 50 The value (nM) reaches 1000nM or less, preferably 500nM or less, and more preferably 100nM or less. Therefore, the compounds of the present invention can be used to treat TRPV3-related skin diseases, such as skin diseases caused by TRPV3 overexpression, such as pruritus and inflammation.

[0121] Using the above methods and materials, the IC values ​​of the typical compounds of the present invention for inhibiting mTRPV3 (mouse TRPV3) and other TRP channels hTRPV1, mTRPV4 and hTRPA1 were also determined under the same conditions. 50 The results are shown in Table 2 below.

[0122] Table 2. In vitro selectivity data of the tested compounds

[0123] From the above results, it can be seen that the inhibitory activity of the compounds of the present invention against TRPV3 is several dozen times stronger than that against TRPV1, TRPV4 and TRPA1. This indicates that the compounds of the present invention are highly selective for TRPV3 and can be used as a specific and highly effective TRPV3 inhibitor.

[0124] Thus, the compounds of the present invention can effectively target the overexpression of TRPV3 without affecting the expression of other TRPs. Of particular note, when the compounds of the present invention are used to treat TRPV3-related skin diseases, such as skin diseases caused by TRPV3 overexpression, such as pruritus and inflammation, they can specifically target the overexpression of TRPV3 without affecting the expression of other TRPs, thereby avoiding side effects on the nervous system, brain, and other tissues.

[0125] Test Example 2. Pruritus Pharmacodynamics Experiment

[0126] Methods and Materials

[0127] Carvacrol, a skin sensitizer, has been shown to induce pruritus in mice by activating TRPV3 channels. Liu et al. found that carvacrol-induced pruritus in mice was concentration-dependent, whereas no significant pruritus was observed in TRPV3 channel knockout mice. Therefore, the carvacrol-induced pruritus model in mice can be used to evaluate the targeting of compounds to inhibit TRPV3 and their efficacy against pruritus.

[0128] 64 SPF-grade C57BL / 6 mice (male, 6-8 weeks old) were used as experimental animals and randomly divided into 8 groups after adaptive feeding: normal control group, model group, solvent control group, positive control group compound 18 (2% concentration) group, compound 18 (8% concentration) group, compound 25 (2% concentration) group, compound 25 (8% concentration) group, with 8 mice in each group. Two days before the experiment, the animals were punctured on a 2*3 cm scalp at the back of the neck. 2 The area was depilated. Thirty minutes before modeling, the corresponding test substance or vehicle was applied to the depilated area on the nape of the neck according to the corresponding group, at a dose of 50 μl per animal. Thirty minutes after administration of the test substance, all animals except the blank control group received an intradermal injection of 2% carvacrol on the nape of the neck at a dose of 50 μl per animal. The acute pruritus model was established, with scratching of the head with the forepaws, scratching of the trunk with the hind paws, and biting of various body parts as pruritus indicators. Sustained scratching of the modeling area by the hind paws was counted as one scratch. If the animal paused, licked its paw, or put its hind paw down during scratching, it was counted as a second scratch. The number of scratches during the observation period was recorded, with the number of scratches at each time point counted in 5-minute intervals. The total number of scratches within 30 minutes was summarized. The number of scratches recorded for each group within 30 minutes after drug administration is shown in Figure 1.

[0129] The raw data were analyzed using GraphPad software and statistically analyzed using one-way ANOVA. The results are shown in Figure 2. *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.

[0130] From the above results, it can be seen that the model group mice (88.00±13.35) and the solvent control group mice (74.25±13.76) showed obvious itching, which was significantly different from the normal control group (0.75±0.41) (P<0.0001), indicating that the model was successfully established. The positive control compound dexamethasone acetate cream (20.63±3.84) significantly improved the itching behavior, which was significantly different from the model control group (P<0.001). Both 2% and 8% concentrations of compound 18 can reduce the number of itching in mice, reducing it to 34.75.00±14.71 and 42.75±11.42, respectively. Among them, the 2% concentration of compound 18 was significantly different from the solvent control group (74.25±13.76) (P<0.05). Compound 25 at both 2% and 8% concentrations significantly reduced the number of pruritus episodes in mice, decreasing them to 13.00±6.11 and 9.25±2.80, respectively. These reductions were statistically significant compared to the vehicle control group (74.25±13.76) (P<0.0001). Furthermore, the number of pruritus episodes in the Compound 25 group was lower than that in the positive control group, the dexamethasone acetate compound cream. These results demonstrate that Compounds 18 and 25 significantly improve carvacrol-induced pruritus in mice, with Compound 25 exhibiting a superior improvement compared to dexamethasone in a concentration-dependent manner.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof, Wherein: R1 is selected from hydrogen, hydroxy, -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, wherein 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 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- 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 according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: 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, wherein 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 according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: 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, wherein the 5-6 membered heteroaryl, C3-C7 heterocyclic group 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, wherein the 5-6 membered heteroaryl, C3-C7 heterocyclic group 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, 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 is 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; 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 according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: 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 a pharmaceutically acceptable salt thereof 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]imidazol-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 a 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: Condense the substituted 2,3-diamino aromatic ring compound shown by formula a to obtain the compound shown by formula b; subject the compound shown by formula b to a substitution reaction with a haloalkane to obtain the compound shown by formula c; subject the compound shown by formula c to a substitution reaction to obtain the compound shown by general formula (I). Alternatively, the method comprises the following steps: Route 2: A substitution reaction is carried out between the substituted 2-fluoro-1-nitroaromatic ring compound shown in formula a and a primary amine compound to obtain a compound shown in formula b'; the compound shown in formula b' is reacted with an aromatic ring compound to obtain a compound shown in formula c'; the compound shown in formula c' is reduced under hydrogen conditions to obtain a compound shown in formula d; the compound shown in formula d is condensed with a carboxylic acid and then cyclized to obtain a compound shown in general formula (I). Alternatively, the method comprises the following steps: Route 3: A substitution reaction is carried out between the substituted 2-fluoro-1-nitroaromatic ring compound represented by formula a" and a primary amine compound to obtain the compound represented by formula b"; the compound represented by formula b" is reduced under hydrogen conditions to obtain the compound represented by formula c"; the compound represented by formula c" is condensed with a carboxylic acid and then cyclized to obtain the compound represented by formula d"; the compound represented by formula d" is reacted with an aromatic ring compound to obtain the compound represented by general formula (I).

7. A pharmaceutical composition comprising a 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 a 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 a 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 a 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, which skin diseases are preferably selected from chronic pruritus, acute pruritus, atopic dermatitis, psoriasis, eczema, neuropathic pain, Olmsted syndrome, and hereditary palmoplantar keratoderma.

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