Phenylurea derivatives and their use in medicine

Abstract

The present invention relates to phenylurea derivatives, particularly to the structural forms of the compounds, such as free base, isomers, solvates, and pharma- ceutically acceptable salts, the method for preparing the compounds, the compositions containing the compounds, and the therapeutic use thereof.The present invention is based on histamine H3 receptor ligands, and has developed a series of phenylurea derivatives with novel structures, and has carried out a series of related biological experiments on the compounds.All the test results show that the compounds have significant H3 receptor antagonist activity, and can be used as lead compounds to prevent or treat diseases related to H3 receptor.

Description

[Technical field]

[0001] The present invention relates to the medical technology field, and to phenylurea derivatives and their use in medicine, in particular to the structural forms of these compounds, such as free bases, isomers, solvates and pharma- ceutically acceptable salt forms, methods for preparing these compounds, compositions containing these compounds and their use in therapy. [Background technology]

[0002] With the development of the Human Genome Project, the histamine receptor family has expanded to four distinct G protein-coupled receptors (GPCRs): H1, H2, H3 and H4 receptors (Nature Review Drug Discovery, 2005, 4, 107-120). The histamine H3 receptor is highly expressed in the central nervous system and to a lesser extent in the peripheral nervous system.

[0003] Histamine H3 receptors (H3R) are widely expressed in brain regions closely related to memory and cognitive abilities, mainly in the cerebral cortex, hippocampus, amygdala, striatum, etc. Blocking these receptors with selective antagonists / inverse agonists increases the release of neurotransmitters such as acetylcholine, dopamine, and 5-hydroxytryptamine, regulating various neurobehaviors such as learning, memory, wakefulness, and sleep (British Journal of Pharmacology, 2008, 154(6), 1166-1181).

[0004] According to the literature, histamine H3 receptor ligands are used to treat cognitive disorders (British Journal of Pharmacology, 2008, 154(6), 1166-1181), dementia (Drug News Perspective, 2010, 23(2), 99-103), attention deficit hyperactivity disorder, obesity (Indian Journal of Pharmacology, 2001, (33), 17-28), schizophrenia (Biochemical Pharmacology, 2007, 73(8), 1215-1224) and pain (Journal of Pharmacology and Experimental Therapeutics, 2011, 336(1), 30-37).

[0005] At present, histamine H3 receptor ligand compounds are mainly classified into two categories: imidazole ring substituted at the 4(5) position and non-imidazole ring. Compounds containing an imidazole ring have the disadvantages of low blood-brain barrier permeability, interaction with cytochrome P-450 proteins, and toxicity to the liver and eyes. As a patent document relating to a representative compound of the non-imidazole ring system, (1) US20020177589A1 discloses a compound used to regulate a new type of histamine H3 receptor ligand. The compound related to the patent is used for the treatment of Alzheimer's disease and cognitive impairment. A representative compound in the compound is ABT-239, whose clinical trials were discontinued due to the discovery of severe cardiac side effects in clinical trials. (2) WO2012114348A1 discloses a novel compound as a histamine H3 receptor ligand. The compound is used for the treatment of various diseases such as cognitive impairment and dementia. Among the drugs in clinical trials, H3R antagonist / inverse agonist Samelisant (SUVN-G3031) for the treatment of cognitive impairment is currently under development, with the phase 2 clinical trial indication being narcolepsy. Phase 1 clinical trials for the cognitive impairment indication were conducted from 2015 to 2017, but there was no further progress. (3) WO2014030170A1 discloses pyridazinone derivatives as histamine H3 inhibitors, the use of those derivatives as H3 inhibitors, their preparation methods and pharmaceutical compositions thereof. The compounds are used to treat various conditions such as cognitive impairment, sleep / wake disorders, and eating disorders. However, the PK / PD data in the clinical trials were not ideal, leading to the clinical trials being discontinued.

[0006] In summary, several histamine H3 receptor ligand compounds have been disclosed, but at present, the only approved drug in this research and development field is Pitolisant (H3R antagonist / inverse agonist). The indication of the marketed product is narcolepsy. Drugs under development such as SUVN-G3031 are also being studied in phase 2 clinical trials for the indication of narcolepsy, and clinical studies for neurological disorders such as cognitive impairment have ended in failure.

[0007] Therefore, it is a technical problem to be solved by those skilled in the art to search for and discover new chemical substances that have novel structures, are highly safe, and are more effective than drugs such as Pitolisant and SUVN-G3031 for use in the prevention or treatment of diseases associated with the H3 receptor. Summary of the Invention

[0008] The present invention aims to provide a phenylurea derivative having a novel structure, which can be used as a histamine H3 receptor ligand compound for the prevention or treatment of diseases associated with the H3 receptor.

[0009] In order to achieve the above objectives, the present invention provides the following technical solutions. A phenylurea derivative, which is a compound having the following structural formula I or a pharma- ceutically acceptable salt thereof: [ka] wherein X is selected from O or S; m is selected from 0, 1, 2, 3, 4, 5 or 6; A is C 1-6 is one selected from an alkyl group, -NR'R'', a substituted or unsubstituted 5-8 membered heterocyclic group, and a substituted or unsubstituted 5-8 membered heteroaryl group, and the heterocyclic group and heteroaryl group have at least one substituent, and the substituent is selected from the group consisting of C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, halogen, amino group, hydroxyl group, cyano group, amide group, sulfone group, sulfoxide group, C 1-6 Halogenated alkyl groups, C 1-6 Alkyl hydroxyl group, C 1-6 Alkylamino group, C 1-6 Alkylamide group, C 1-6 Alkyl sulfone group, C 1-6 Alkyl sulfoxide group, C 1-6 Halogenated alkoxy groups, C 1-6Alkoxyhydroxyl group, C 1-6 Alkoxyamino group, C 1-6 Alkoxyamide group, C 1-6 Alkoxysulfonic acid group, C 1-6 one or more selected from an alkoxysulfoxide group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, and a heteroaryl group; R' and R'' are each independently hydrogen, C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen, amino group, hydroxyl group, carboxyl group, carbonyl group, amide group, cyano group, C 1-6 Halogenated alkyl groups, C 1-6 Alkyl hydroxyl group, C 1-6 Alkylamino group, C 1-6 Alkylamide group, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxyhydroxyl group, C 1-6 Alkoxyamino group, C 1-6 one or more selected from alkoxyamide groups, and R' and R'' are not hydrogen at the same time; R1 and R2 are each independently hydrogen or C 1-6 -alkyl group, -C(O)-alkyl group or -S(O)-alkyl group, R3, R4, R5, and R6 are each independently hydrogen, halogen, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, amino group, hydroxyl group, cyano group, amide group, sulfone group, sulfoxide group, C 1-6 Halogenated alkyl groups, C 1-6 Alkyl hydroxyl group, C 1-6 Alkylamino group, C 1-6 Alkylamide group, C 1-6 Alkyl sulfone group, C 1-6 alkyl sulfoxide groups, or R3 and R4 together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring structure, including, but not limited to, a benzoheterocycle; or R5 and R6 together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring structure, including, but not limited to, a benzoheterocycle; The heterocyclic, heteroaryl and benzoheterocycle groups contain at least one heteroatom, which is selected from N, O or S.

[0010] Preferably, the phenylurea derivative is a compound having the following structural formula II or a pharma- ceutically acceptable salt thereof: [ka] wherein X is selected from O or S; m is selected from 0, 1, 2, 3, 4, 5 or 6; A is one selected from a substituted or unsubstituted 5-8 membered heterocyclic group and a substituted or unsubstituted 5-8 membered heteroaryl group, and the heterocyclic group and the heteroaryl group have at least one substituent, and the substituent is selected from the group consisting of C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, halogen, amino group, hydroxyl group, cyano group, amide group, sulfone group, sulfoxide group, C 1-6 Halogenated alkyl groups, C 1-6 Alkyl hydroxyl group, C 1-6 Alkylamino group, C 1-6 Alkylamide group, C 1-6 Alkyl sulfone group, C 1-6 Alkyl sulfoxide group, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxyhydroxyl group, C 1-6 Alkoxyamino group, C 1-6 Alkoxyamide group, C 1-6 Alkoxysulfonic acid group, C1-6 one or more selected from an alkoxysulfoxide group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, and a heteroaryl group; R3, R4, R5, and R6 are each independently hydrogen, halogen, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, amino group, hydroxyl group, cyano group, amide group, sulfone group, sulfoxide group, C 1-6 Halogenated alkyl groups, C 1-6 Alkyl hydroxyl group, C 1-6 Alkylamino group, C 1-6 Alkylamide group, C 1-6 Alkyl sulfone group, C 1-6 alkyl sulfoxide groups, or R3 and R4 together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring structure, including, but not limited to, a benzoheterocycle; or R5 and R6 together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring structure, including, but not limited to, a benzoheterocycle; The heterocyclic, heteroaryl and benzoheterocycle groups contain at least one heteroatom, which is selected from N, O or S.

[0011] Preferably, the phenylurea derivative is a compound having the following structural formula II-1 or a pharma- ceutically acceptable salt thereof: [ka] wherein m is selected from 1, 2, 3, 4, 5, or 6; A is one selected from a substituted or unsubstituted 6-membered heterocyclic group and a substituted or unsubstituted 6-membered heteroaryl group, and the heterocyclic group and the heteroaryl group have at least one substituent, and the substituent is selected from the group consisting of C 1-6 Alkyl group, C 1-6Alkoxy group, halogen, amino group, hydroxyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkyl hydroxyl group, C 1-6 Alkylamino group, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxyhydroxyl group, C 1-6 one or more selected from alkoxyamino groups, R3, R4, R5, and R6 are each independently hydrogen, halogen, or C 1-6 Alkyl group, amino group, hydroxyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkyl hydroxyl group, C 1-6 alkylamino groups, The heterocyclic and heteroaryl groups contain at least one heteroatom, which is selected from N, O or S.

[0012] Preferably, the phenylurea derivative is a compound having the following structural formula III or a pharma- ceutically acceptable salt thereof: [ka] wherein m is selected from 1, 2, 3, 4, 5, or 6; R' and R'' are each independently hydrogen, C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen, amino group, hydroxyl group, carboxyl group, carbonyl group, amide group, cyano group, C 1-6 Halogenated alkyl groups, C 1-6 Alkyl hydroxyl group, C 1-6 Alkylamino group, C 1-6 Alkylamide group, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxyhydroxyl group, C 1-6 Alkoxyamino group, C 1-6 one or more selected from alkoxyamide groups, and R' and R'' are not hydrogen at the same time; R3, R4, R5, and R6 are each independently hydrogen, halogen, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, amino group, hydroxyl group, cyano group, amide group, sulfone group, sulfoxide group, C 1-6 Halogenated alkyl groups, C 1-6 Alkyl hydroxyl group, C 1-6 Alkylamino group, C 1-6 Alkylamide group, C 1-6 Alkyl sulfone group, C 1-6 alkyl sulfoxide groups, or R3 and R4 together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring structure, including, but not limited to, a benzoheterocycle; or R5 and R6 together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring structure, including, but not limited to, a benzoheterocycle; The benzoheterocycle contains at least one heteroatom, which is selected from N, O or S.

[0013] Preferably, the phenylurea derivative is a compound having the following structural formula IV or a pharma- ceutically acceptable salt thereof: [ka] In the formula, A is C 1-6 alkyl groups, R3, R4, R5, and R6 are each independently hydrogen, halogen, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, amino group, hydroxyl group, cyano group, amide group, sulfone group, sulfoxide group, C 1-6 Halogenated alkyl groups, C 1-6 Alkyl hydroxyl group, C 1-6 Alkylamino group, C 1-6 Alkylamide group, C1-6 Alkyl sulfone group, C 1-6 alkyl sulfoxide groups, or R3 and R4 together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring structure, including, but not limited to, a benzoheterocycle; or R5 and R6 together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring structure, including, but not limited to, a benzoheterocycle; The benzoheterocycle contains at least one heteroatom, the heteroatom being selected from N, O or S.

[0014] The present invention provides phenylurea derivatives including compounds having the following structures, isomers, solvates or pharma- ceutically acceptable salts thereof, numbered BIOS-A-1 to BIOS-A-23: BIOS-A-1: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-cyclopentyl urea, BIOS-A-2: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-cyclohexylurea, BIOS-A-3: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-morpholinylethyl)urea, BIOS-A-4: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(piperidin-1-yl)ethyl)urea, BIOS-A-5: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)urea, BIOS-A-6: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(2-methylpyrrolidin-1-yl)ethyl)urea, BIOS-A-7: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(4,4-difluoropiperidin-1-yl)ethyl)urea, BIOS-A-8: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(thiomorpholinylethyl)urea, BIOS-A-9: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(4-hydroxypiperidin-1-yl)ethyl)urea, BIOS-A-10: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea, BIOS-A-11: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(4-isopropylpiperazin-1-yl)ethyl)urea, BIOS-A-12: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(3-hydroxypiperidin-1-yl)ethyl)urea, BIOS-A-13: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(N-methylhomopiperazin-1-yl)ethyl)urea, BIOS-A-14: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(piperazin-1-yl)ethyl)urea, BIOS-A-15: 1-(2-(4-cyclobutylpiperazin-1-yl)ethyl)-3-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)urea, BIOS-A-16: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-isopropylurea, BIOS-A-17: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(dimethylamino)ethyl)urea, BIOS-A-18: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(diethylamino)ethyl)urea, BIOS-A-19: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(ethylamino)ethyl)urea, BIOS-A-20: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-morpholinylethyl)thiourea, BIOS-A-21: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(piperidin-1-yl)ethyl)thiourea, BIOS-A-22: 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)thiourea, or BIOS-A-23: (R)-1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(2-methylpyrrolidin-1-yl)ethyl)thiourea

[0015] The structural formulae of the compounds numbered BIOS-A-1 to BIOS-A-23 above or pharma- ceutically acceptable salts thereof are as follows: [ka]

[0016] The present invention further provides phenylurea derivatives, including chiral compounds having the following structure: or a pharma- ceutically acceptable salt thereof: (R)-1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(2-methylpyrrolidin-1-yl)ethyl)urea, or (R)-1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(2-methylpyrrolidin-1-yl)ethyl)thiourea

[0017] The "compound" according to the present invention includes, but is not limited to, a free base, a stereoisomer, a geometric isomer, a tautomer, an isotope, a pharma- ceutically acceptable salt thereof, a solvate, a hydrate, and a prodrug (an ester or a phosphate ester).

[0018] The "compound" according to the present invention may be asymmetric in structure. For example, it may have one or more stereoisomers. Unless otherwise specified, all stereoisomers include enantiomers and diastereomers. In addition, in the present invention, compounds having asymmetric carbon atoms may be separated in optically pure form or racemic form. Optically pure forms can be obtained by separation of racemic forms or by synthetic methods using chiral starting materials or chiral reagents.

[0019] The "pharmaceutically acceptable salt" according to the present invention means that the salt of the compound of the present invention is prepared from a compound having a specific substituent discovered in the present invention and a relatively non-toxic base. When the compound of the present invention contains a relatively acidic functional group, the neutral form of the compound is contacted with a sufficient amount of base in a pure solution or a suitable inert solvent to obtain a base addition salt. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium or organic ammonia addition salts. For example, alkali metal salts, alkaline earth metal salts, other metal salts, inorganic alkali salts, organic alkali salts, inorganic acid salts, lower alkane sulfonate salts, etc.

[0020] In addition to the salt form, the compounds provided by the present invention may be in the form of prodrugs. Prodrugs of the compounds described herein are easily converted to the compounds of the present invention under physiological conditions by chemical or biochemical methods in an in vivo environment.

[0021] For compounds having the structural formula set forth above, the terms used herein have the following meanings: The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0022] The term "alkyl group" means C 1-6 Alkyl refers to a straight or branched chain saturated hydrocarbon group composed of carbon atoms and hydrogen atoms, including, but not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), n-hexyl, and 2-methylhexyl.

[0023] The term "cycloalkyl group" means 3-8 Cycloalkyl groups refer to monocyclic or bicyclic alkyl groups consisting of carbon atoms and hydrogen atoms, such as cycloalkyl groups, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0024] The term "alkoxy group" means 1-6 It refers to a straight or branched chain alkyl group bonded through an oxygen atom, such as an alkoxy group, including, but not limited to, methoxy, ethoxy, n-propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy, and neopentyloxy), n-hexyloxy, and 2-methylhexyloxy.

[0025] The term "alkylamino group" means 1-6 This refers to an open chain alkyl group containing a nitrogen atom, such as an alkylamino group, including, but not limited to, methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, and the like.

[0026] The term "aryl group" refers to an all-carbon monocyclic or fused polycyclic group of 5 to 12 (integer) carbon atoms. Aryl groups have a completely conjugated pi-electron system. Examples include, but are not limited to, a benzene ring, a naphthalene ring, and an anthracene ring.

[0027] The terms "heterocyclyl group" and "heteroaryl group" refer to a monocyclic or fused ring having 3 to 12 (integer) ring atoms, in which one, two, three or more ring atoms are one or more selected from N, O, and S, and the remaining ring atoms are C, and have a fully conjugated or non-conjugated π-electron system. Heterocyclyl groups may be saturated or unsaturated. Heterocyclyl groups include, but are not limited to, pyrrolyl, indolyl, pyrrolidinyl, imidazolyl, pyrazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolyl, piperidinyl, pyrimidinyl, pyrazinyl, piperazinyl, furyl, pyranyl, and morpholinyl groups.

[0028] The method for preparing the above compound in the present invention is carried out through the following steps, but is not limited to this method. [ka] The reaction process is as follows: p-Fluoronitrobenzene compound (raw material 1), piperidinol, and sodium hydride were dissolved in DMF, reacted, and reacted in a hydrochloric acid / ethyl acetate solution to obtain intermediate 1. Then, intermediate 2 was obtained by reductive amination with o-cyclobutanone, and intermediate 3 was obtained by reduction reaction in a Pd / C hydrogen atmosphere. Furthermore, intermediate 3 was reacted with isocyanate in dichloromethane to obtain the target compound. Alternatively, intermediate 3 can be reacted with a chlorinated isocyanate in dichloromethane to give intermediate 4, which can then be reacted with an amine to give intermediate 5 or the target compound. Alternatively, intermediate 5 is reacted with Lawesson's reagent to obtain the target compound.

[0029] The substituents R', R'', R3, R4, R5, and R6 in the above-mentioned synthesis methods are defined as follows: R' and R'' are each independently hydrogen, C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen, amino group, hydroxyl group, carboxyl group, carbonyl group, amide group, cyano group, C 1-6 Halogenated alkyl groups, C 1-6 Alkyl hydroxyl group, C 1-6 Alkylamino group, C 1-6 Alkylamide group, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxyhydroxyl group, C 1-6 Alkoxyamino group, C 1-6 The alkoxyamide group is one or more groups selected from the group consisting of alkoxyamide groups, and R' and R'' cannot simultaneously be hydrogen. R3, R4, R5, and R6 are each independently hydrogen, halogen, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, amino group, hydroxyl group, cyano group, amide group, sulfone group, sulfoxide group, C 1-6 Halogenated alkyl groups, C 1-6 Alkyl hydroxyl group, C 1-6 Alkylamino group, C 1-6 Alkylamide group, C 1-6 Alkyl sulfone group, C 1-6 alkyl sulfoxide groups. Alternatively, R3 and R4 together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic structure, including but not limited to benzoheterocycles. Alternatively, R5 and R6 together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic structure, including but not limited to benzoheterocycles.

[0030] The present invention further provides pharmaceutical compositions comprising at least one of the aforementioned compounds or a pharma- ceutically acceptable salt thereof as an active ingredient, together with at least one pharma- ceutically acceptable carrier or excipient.

[0031] In the present invention, the term "pharmaceutical composition" refers to a preparation of one or more compounds of the present invention or salts thereof and a carrier generally accepted in the art for delivering biologically active compounds to an organism (such as a human). The pharmaceutical composition is intended to facilitate delivery of a drug to an organism.

[0032] The routes of administration of the compounds of the present invention, their pharma- ceutically acceptable salts, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, mucosal, enteral, topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous. The preferred route of administration is oral.

[0033] The invention provides the use of said compound or pharmaceutical composition in the prevention or treatment of diseases associated with the histamine H3 receptor.

[0034] Preferably, the pharmaceutical composition is used for the prevention or treatment of cognitive impairment, dementia, attention deficit hyperactivity disorder, schizophrenia, epilepsy, sleep disorder, sleep apnea syndrome, obesity, eating disorder, pain and pruritus.

[0035] Preferably, the pharmaceutical composition is used for the prevention or treatment of neuropathic pain, including but not limited to peripheral neuropathic pain or central neuropathic pain.

[0036] More preferably, the peripheral neuropathic pain is trigeminal neuralgia, glossopharyngeal neuralgia, acute or chronic inflammatory demyelinating polyradiculoneuropathy, alcoholic polyneuropathy, chemotherapy-induced polyneuropathy, complex regional pain syndrome, entrapment neuralgia (such as carpal tunnel syndrome), HIV sensory neuralgia, iatrogenic neuralgia (such as post-mastectomy pain), tumor compression or infiltration neuralgia, nutritional deficiency neuralgia, diabetic neuralgia, phantom limb pain, post-herpetic neuralgia, post-radiotherapy plexus pain, radiculopathy (cervical, thoracic, or lumbosacral), neuralgia associated with toxic exposure, or post-traumatic neuralgia.

[0037] More preferably, the central neuropathic pain is post-stroke pain, multiple sclerosis associated pain, Parkinson's disease associated pain, pain after traumatic spinal cord injury, syringomyelia, post-ischemic myelopathy, compressive myelopathy, HIV myelopathy, or post-radiation myelopathy.

[0038] Compared with the prior art, the present invention has the following beneficial effects: The present invention has developed a series of phenylurea derivatives with novel structures based on histamine H3 receptor ligands. The compounds have simple synthesis routes and are easy to obtain raw materials. In addition, a series of relevant biological experiments have been carried out on the compounds of the present invention. All the test results show that the compounds have significant H3 receptor antagonist activity, and can be used as lead compounds to prevent or treat diseases related to H3 receptor. [Brief description of the drawings]

[0039] [Figure 1] The change in mechanical tingle pain threshold for each experimental group at different times and at different doses is shown.

[0040] In Figure 1, when comparing with the model group, * P < 0.05, ** indicates P<0.01, when compared with the sham group. # P < 0.05, ## indicates P<0.01. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] The following provides specific embodiments to further illustrate the technical solutions of the present invention, but the protection scope of the present invention is not limited to these embodiments. Any modifications or equivalent replacements that do not depart from the technical spirit of the present invention are included in the protection scope of the present invention.

[0042] The solvents, equipment, abbreviations and names used in the examples of the present invention are as follows. Abbreviation Bn: benzyl group Abbreviation DMF: Reagent N,N-Dimethylformamide Abbreviation TFA: Trifluoroacetic acid Abbreviation: TsCl: p-toluenesulfonyl chloride Abbreviation TEA: Triethylamine reagent Abbreviation DCM: Dichloromethane Abbreviation: Boc: tert-butoxycarbonyl group Abbreviated name: Lawesson reagent: 2,4-bis(p-methoxyphenyl)-1,3-dithiadiphosphetane-2,4 sulfide

[0043] In the preparation method of the target compound of the present invention, a Waters Symmetry C18 column was used for liquid chromatography, and GF254 (0.25 mm) was used for thin layer chromatography. Nuclear magnetic resonance chromatography (NMR) was measured by a Bruker-400 nuclear magnetic resonance device, and liquid chromatography mass spectrometry (LC / MS) was measured by a Waters ZQ mass spectrometer detector (column: Waters Symmetry C18, mm, 5 μm, 35 ° C). The ESI (+) ion model was adopted.

[0044] In addition, when raw materials that are easily oxidized or hydrolyzed are used, all operations are carried out under nitrogen protection. Unless otherwise stated, in the present invention, all raw materials used are commercially available raw materials and are used as they are without further purification.

[0045] Various reaction raw materials, common intermediates, etc. according to the embodiments of the present invention are commercially available products or obtained by preparation, and the raw materials and common intermediates obtained by preparation are prepared as follows.

[0046] 1. Preparation of common intermediate A1 The synthetic route of intermediate A1 is as follows. [ka]

[0047] Step 1: Synthesis of 4-(4-nitrophenoxy)piperidine (3) In a 500 mL eggplant flask, N-Boc-4-hydroxypiperidine (compound 2, 5.14 g, 25.51 mmol) was dissolved in anhydrous N,N-dimethylformamide (40 mL), and sodium hydride powder (1.02 g, 25.51 mmol) was added under nitrogen protection in an ice-water bath, and the reaction was allowed to proceed for 1 h. Finally, a solution of 4-fluoronitrobenzene (compound 1, 3.0 g) and anhydrous N,N-dimethylformamide (5 mL) was added dropwise, and after the completion of the dropwise addition, the reaction was allowed to proceed for 6 h at room temperature. It was detected by thin layer chromatography that the raw materials had essentially completely reacted. The reaction solution was quenched by adding water (320 mL) and mixed uniformly, extracted three times with ethyl acetate, and the organic phases were combined, washed with saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 9.56 g of a crude brown liquid.

[0048] The crude product was dissolved in hydrochloric acid-ethyl acetate (30 mL) and reacted at room temperature for 1-2 h. The complete reaction of the raw material was detected by thin layer chromatography. The reaction solution was filtered, the filter cake was washed with a small amount of ethyl acetate, and the filter cake was dried to obtain 5.55 g of a white solid (i.e., compound 3) (yield 84.10%). MS: 223.1[M+H]+.

[0049] Step 2: Synthesis of 1-cyclobutyl-4-(4-nitrophenoxy)piperidine (5) Compound 3 (5.55 g, 21.45 mmol) was mixed with 40 mL of anhydrous methanol, and after adding 3 mL of triethylamine, it was completely dissolved. Then, cyclobutanone (compound 4, 2 mL) and acetic acid (2 mL) were added, and the mixture was stirred for 1 h at low temperature in an ice-water bath. 2.1 g of sodium cyanoborohydride was added, and finally, the mixture was reacted overnight at room temperature for 12 h. The raw material was detected to have completely reacted by thin layer chromatography.

[0050] The reaction solution was concentrated under reduced pressure, alkalized to pH 8-9 with sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain 6.77 g of a yellow solid (i.e., compound 5) (yield 99%). MS: 277.1[M+H]+.

[0051] Step 3: Synthesis of 4-((1-cyclobutylpiperidin-4-yl)oxy)aniline (A1) Compound 5 (6.77 g, 24.50 mmol) was mixed with 180 mL of ethanol solution, and 9.6 g of reduced iron powder, 2.36 g of ammonium chloride, and 60 mL of water were added, and the mixture was reacted in an oil bath at 80° C. for 2 to 3 hours. Complete reaction of the raw materials was detected by thin layer chromatography.

[0052] The reaction solution was filtered through diatomaceous earth, the filter cake was washed 4-5 times with ethanol, the filtrate was concentrated and dried, sodium carbonate solution was added to alkalize it to pH 9-10, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain 4.99 g of a yellow-brown liquid (i.e., intermediate A1) (yield 82.68%). MS:247.1[M+H] + .

[0053] II. Preparation of common intermediate A2: The synthetic route of intermediate A2 is as follows. [ka] Intermediate A1 (300 mg, 1.242 mmol) and pyridine (150 mL, 1.491 mmol) were dissolved in 8 mL of anhydrous dichloromethane, stirred at low temperature in an ice-water bath for 10 min, added dropwise with 187 μL of phenyl chloroformate, and finally reacted at room temperature for 2-3 h. Thin layer chromatography detected that the raw materials had completely reacted.

[0054] The reaction solution was concentrated and dried, alkalized to pH 8-9 with sodium carbonate solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain 480 mg of a brown crude product (i.e., intermediate A2) (yield 100%). MS:367.2[M+H] + .

[0055] 3. Preparation of common intermediate A3: The synthetic route to intermediate A3 is as follows. [ka] Intermediate A1 (2.01 g, 8.16 mmol) was dissolved in 20 mL of anhydrous dichloromethane, stirred for 10 min at low temperature in an ice-water bath, added 835 μL of chloroethyl isocyanate dropwise, and finally reacted at room temperature for 3 to 4 h. Thin layer chromatography detected that the raw material had completely reacted.

[0056] The reaction solution was filtered, and the filter cake was washed with a small amount of dichloromethane and dried to obtain 1.96 g of a white powder (ie, intermediate A3) (yield 68.26%). MS:352.3[M+H] + .

[0057] The following Examples 1 to 23 are preparation examples of the free radical and / or hydrochloride structure of the BIOS-A compounds of the present invention. In addition to the hydrochloride form described in the Examples, the BIOS-A compounds may be in the form of pharma- ceutically acceptable salts thereof, including but not limited to sulfates, nitrates, nitrites, maleates, fumarates, formates, diformates, acetates, etc. All of the methods for preparing these salts are suggested by the technical ideas of the Examples 1 to 23 provided by the present invention.

[0058] Example 1: Synthesis of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-cyclopentylurea (BIOS-A-1) [ka] The synthetic route is as follows: [ka] Intermediate A1 (100 mg, 0.406 mmol) and cyclopentyl isocyanate (46 μL, 0.406 mmol) were dissolved in 4 mL of dichloromethane and reacted at room temperature for 4 to 5 h. Thin layer chromatography was used to detect that the raw materials had completely reacted.

[0059] The reaction solution was filtered, and the filter cake was washed with a small amount of dichloromethane to obtain 90 mg of a white solid (ie, compound BIOS-A-1) (yield 62.00%). MS:358.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.24(d,J=8.6Hz,2H),6.80(d,J=8.6Hz,2H),6.06(d,J=7.2Hz, 1H), 4.27~4.11(m,1H),3.98~3.85(m,1H),2.73~2.62(m,1H),2.05~1.46(m,20H),1.39~1.28(m,2H).

[0060] Example 2: Synthesis of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-cyclohexylurea (BIOS-A-2) [ka] The synthetic route is as follows: [ka] Intermediate A2 (260 mg, 0.709 mmol), cyclohexylamine (97 μL, 0.851 mmol), and 197 μL of triethylamine were dissolved in 4 mL of acetonitrile solution and reacted at room temperature overnight. The reaction was detected by thin layer chromatography to confirm that the raw materials had reacted completely.

[0061] The reaction solution was concentrated and dried, and the crude product was purified on a separation plate (petroleum ether:ethyl acetate:triethylamine=1:1:0.1) to obtain 116 mg of a yellow solid (i.e., compound BIOS-A-2) (yield 44.04%). MS:372.5[M+H] + .

[0062] 1 H NMR(400MHz,DMSO-d6)δ8.61(s,1H),7.29(d,J=8.6Hz,2H),6.89(d,J=8.6Hz,2H),6.29(s,1H),4.68~4.32(m,1H), 3.43(s,1H),2.89~2.54(m,4H),2.40(s,2H),2.14(s,4H),2.05~1.83(m,3H),1.82~1.47(m,8H),1.37~1.23(m,4H).

[0063] Example 3: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-morpholinylethyl)urea (BIOS-A-3) [ka] The synthetic route is as follows: [ka] Intermediate A3 (100 mg, 0.284 mmol), morpholine (100 μL, 0.853 mmol), and 197 μL of triethylamine were dissolved in 4 mL of acetonitrile solution and reacted for 2 to 3 hours at 80° C. in an oil bath. The reaction was detected by thin layer chromatography to confirm that the raw materials had completely reacted.

[0064] The reaction solution was concentrated and dried, and the crude product was purified on a preparative plate (petroleum ether:ethyl acetate:triethylamine=1:4:1) to obtain 48 mg of a white solid (i.e., compound BIOS-A-3) (yield 41.99%). MS:403.1[M+H] + .

[0065] 1 H NMR(400MHz,DMSO-d6)δ=8.43(s,1H),7.25(d,J=9.0Hz,2H),6.81(d,J=9.0Hz,2H),5.99(t,J=5.4Hz,1H),4.26~4.16(m,1H),3.59(t,J=4.6Hz,4 H),3.18(q,J=6.2Hz,2H),2.74~2.61(m,1H),2.60~2.52(m,2H),2.37(t ,J=5.6Hz,6H),2.07~1.83(m,6H),1.83~1.69(m,2H),1.64~1.50(m,4H).

[0066] Example 4: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(piperidin-1-yl)ethyl)urea (BIOS-A-4) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that in this example piperidine is used instead of morpholine in Example 3, preparation steps are the same as in Example 3. Obtain 76mg of white solid (i.e. compound BIOS-A-4) (yield 66.81%). MS:401.2[M+H] + .

[0067] 1 H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.26(d,J=8.8Hz,2H),6.81(d,J=8.8Hz,2H),6.13(s,1H),4.28~4.16(m,1H),3.23~3.13(m,2H),2.82~2.69 (m,1H),2.60(d,J=5.4Hz,2H),2.47~2.36(m,6H),2.09~2.06(m,2H),2.0 2~1.85(m,4H),1.85~1.73(m,2H),1.65~1.50(m,8H),1.45~1.34(m,2H).

[0068] Example 5: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)urea (BIOS-A-5) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that in this example, tetrahydropyrrole is used instead of morpholine in Example 3, the preparation steps are the same as in Example 3. Obtain 32mg of white solid (i.e. compound BIOS-A-5) (yield 29.15%). MS:401.2[M+H] + .

[0069] 1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.25(d,J=8.8Hz,2H),6.80(d,J=8.8Hz,2H),6.00(t,J=5.4Hz,1H),4.26~4.14(m, 1H), 3.21~3.14(m,2H),2.72~2.62(m,1H),2.61~2.52(m,2H),2.50~2.37(m,8H),2.05~1.91(m,4H),1.79~1.48(m,10H).

[0070] Example 6: Preparation of (R)-1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(2-methylpyrrolidin-1-yl)ethyl)urea (BIOS-A-6) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that in this example, (R)-2-methylpyrrolidine is used instead of morpholine in Example 3, the preparation steps are the same as in Example 3. Obtain 74mg of yellow solid (i.e., compound BIOS-A-6) (yield 65.05%). MS:387.1[M+H] + .

[0071] 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),7.26(d,J=8.6Hz,2H),6.81(d,J=8.6Hz,2H),6.05(s,1H),4.23(s,1H),2.89(d,J=9.3Hz,2H),2.76(t,J=7.8Hz, 1H),2.61(s,2H),2.45(s,2H),2.21(d,J=9.0Hz,2H),2.14~2.04(m,2H),2 .02~1.86(m,6H),1.85~1.50(m,6H),1.40~1.30(m,1H),1.16~1.03(m,5H).

[0072] Example 7: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(4,4-difluoropiperidin-1-yl)ethyl)urea (BIOS-A-7) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that in this example, 4,4-difluoroperidine is used instead of morpholine in Example 3, the preparation steps are the same as in Example 3. Obtain 100mg of white solid (i.e. compound BIOS-A-7) (yield 80.66%). MS:437.2[M+H] + .

[0073] 1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.28(d,J=9.0Hz,2H),6.85(d,J=8.6Hz,2H),6.07(s,1H),4.37(s,1H),3.19(q,J=6 .2Hz,2H),3.10~3.00(m,1H),2.85(s,2H),2.60~2.50(m,7H),2.48~2.42(m,2H),2.20~1.87(m,10H),1.74~1.55(m,3H).

[0074] Example 8: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(thiomorpholin-1-yl)ethyl)urea (BIOS-A-8) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that in this example, thiomorpholine is used instead of morpholine in Example 3, the preparation steps are the same as in Example 3. Obtain 73mg of white solid (i.e., compound BIOS-A-8) (yield 61.41%). MS:419.2[M+H] + .

[0075] 1 H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.25(d,J=9.0Hz,2H),6.81(d,J=9.0Hz,2H),5.93(t,J=5.4Hz,1H),4.27~4.16(m,1H) ,3.16(q,J=6.1Hz,2H),2.79~2.54(m,11H),2.40(t,J=6.4Hz,2H),2.14~1.84(m,6H),1.84~1.71(m,2H),1.68~1.49(m,4H).

[0076] Example 9: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(4-hydroxypiperidin-1-yl)ethyl)urea (BIOS-A-9) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that in this example, 4-hydroxypiperidine is used instead of morpholine in Example 3, the preparation steps are the same as in Example 3. Obtain 107mg of white solid (i.e., compound BIOS-A-9) (yield 90.45%). MS:417.2[M+H] + .

[0077] 1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),7.26(d,J=9.0Hz,2H),6.82(d,J=9.0Hz,2H),5.98(s,1H),4.60(s,1H),4.24( s,1H),3.47(s,1H),3.18(d,J=5.9Hz,2H),2.82~2.42(m,5H),2.40(s,2H),2.24~1.68(m,12H),1.67~1.35(m,6H).

[0078] Example 10: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea (BIOS-A-10) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that in this example, 4-methylpiperazine is used instead of morpholine in Example 3, the preparation steps are the same as in Example 3. Obtain 103 mg of white solid (i.e., compound BIOS-A-10) (yield 87.27%). MS:416.2[M+H] + .

[0079] 1 H NMR(400MHz,DMSO-d6)δ8.46(s,1H),7.25(d,J=9.0Hz,2H),6.81(d,J=9.0Hz,2H),5.95(t,J=5.4Hz,1H),4.26~4.16(m,1H),2.98~2.90(m,2H), 2.77~2.65(m,1H),2.58(t,J=5.9Hz,2H),2.40~2.25(m,8H),2.19(s,2H) ),2.16(s,3H),2.08~1.84(m,6H),1.84~1.71(m,2H),1.67~1.48(m,4H).

[0080] Example 11: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(4-isopropylpiperazin-1-yl)ethyl)urea (BIOS-A-11) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that in this example, 4-isopropylpiperazine is used instead of morpholine in Example 3, the preparation steps are the same as in Example 3. Obtain 114mg of pale yellow solid (i.e., compound BIOS-A-11) (yield 90.48%). MS:444.3[M+H] + .

[0081] 1 H NMR(400MHz,DMSO-d6)δ8.44(s,1H),7.25(d,J=9.0Hz,2H),6.81(d,J=9.0Hz,2H),5.94(t,J=5.5Hz,1H),4.23(s,1H), 3.17(q,J=6.0Hz,2H),2.84~2.54(m,5H),2.48~2.27(m,7H),2.17~1.69(m,9H),1.67~1.49(m,4H),1.06~0.88(m,7H).

[0082] Example 12: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(3-hydroxypiperidin-1-yl)ethyl)urea (BIOS-A-12) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that in this example, 3-hydroxypiperidine is used instead of morpholine in Example 3, the preparation steps are the same as in Example 3. Obtain 92mg of white solid (i.e. compound BIOS-A-12) (yield 77.77%). MS:417.2[M+H] + .

[0083] 1 H NMR(600MHz,DMSO-d6)δ8.40(s,1H),7.24(d,J=9.0Hz,2H),6.80(d,J=9.0Hz,2H),5.92(t,J=5 .4Hz,1H),4.58(d,J=5.0Hz,1H),4.24~4.16(m,1H),3.51~3.44(m,1H),3.15(q,J=6.1Hz,2H), 2.82(d,J=10.8Hz,1H),2.73~2.62(m,2H),2.57(s,2H),2.41~2.30(m,2H),2.07~1.92(m,4H), 1.91~1.82(m,3H),1.81~1.71(m,4H),1.65~1.50(m,5H),1.46~1.36(m,1H),1.13~1.03(m,1H).

[0084] Example 13: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(N-methylhomopiperazin-1-yl)ethyl)urea (BIOS-A-13) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that in this example, N-methylhomopiperazine is used instead of morpholine in Example 3, the preparation steps are the same as in Example 3. Obtain 84mg of white solid (i.e., compound BIOS-A-13) (yield 68.85%). MS:430.2[M+H] + .

[0085] 1 H NMR(400MHz,DMSO-d6)δ8.49(s,1H),7.25(d,J=9.0Hz,2H),6.81(d,J=9.0Hz,2H),5.99(s,1H),4.26 ~4.15(m,1H),3.17~3.03(m,5H),2.78~2.63(m,10H),2.35(s,3H),2.31(s,2H),2.09~1.70(m,12H).

[0086] Example 14: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(piperazin-1-yl)ethyl)urea (BIOS-A-14) [ka] The synthetic route is as follows: [ka] Intermediate A3 (100 mg, 0.284 mmol), 1-Boc-piperazine (158 mg, 0.853 mmol), and 197 μL of triethylamine were dissolved in 4 mL of acetonitrile and reacted for 2 to 3 hours at 80° C. in an oil bath. The reaction was detected by thin layer chromatography to confirm that the raw materials had completely reacted.

[0087] The reaction solution was concentrated and dried, and the crude product was purified on a preparative plate (petroleum ether: ethyl acetate: triethylamine = 1: 4: 1) to obtain 96 mg of a white solid intermediate. The intermediate was reacted in 3 mL of hydrochloric acid-ethyl acetate for 2 h, filtered, concentrated and dried to obtain 91 mg of a white solid hydrochloride (i.e., the hydrochloride salt of compound BIOS-A-14) (two-step yield 62.71%). MS:402.2[M+H] + .

[0088] 1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.99(d,J=10.2Hz,1H),7.32(d,J=9. 0Hz,2H),6.90(d,J=9.0Hz,2H),6.68(s,1H),3.63~3.55(m,2H),3.54~3.45 (m,4H),3.24(t,J=6.2Hz,2H),3.19~3.13(m,8H),2.96~2.76(m,2H),2.41( t,J=10.2Hz,2H),2.16~2.12(m,4H),2.04~1.85(m,2H),1.80~1.61(m,2H).

[0089] Example 15: Preparation of 1-(2-(4-cyclobutylpiperazin-1-yl)ethyl)-3-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)urea (BIOS-A-15) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that in this example, 1-cyclobutylpiperazine is used instead of morpholine in Example 3, the preparation steps are the same as in Example 3. Obtain 84mg of white solid (i.e., compound BIOS-A-15) (yield 64.91%). MS:456.3[M+H] + .

[0090] 1 H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.26(d,J=8.6Hz,2H),6.83(d,J=8.6Hz,2H),5.95(s,1H),4.27(s,1H),3.18 (d,J=6.1Hz,2H),2.08~2.99(m,1H),2.86~2.58(m,4H),2.42~2.36(m,9H),2.09~1.73(m,12H),1.66~1.62(m,6H).

[0091] Example 16: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-isopropylurea (BIOS-A-16) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-1 in Example 1, except that in this example, isopropyl isocyanate was used instead of cyclopentyl isocyanate in Example 1, and the preparation steps were the same as in Example 1. Obtained 84 mg of white solid (i.e., compound BIOS-A-16) (yield 62.42%). MS:456.3[M+H] + .

[0092] 1 H NMR(400MHz,DMSO-d6)δ8.61(s,1H),7.29(d,J=8.6Hz,2H),6.89(d,J=8.6Hz,2H),6.29(s,1H),4.68~4.32(m,1H) ,4.14~4.09(m,1H),3.43(s,1H),2.05~1.83(m,4H),1.82~1.47(m,6H),1.37~1.23(m,4H),1.15(d,J=5.5Hz,6H).

[0093] Example 17: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(dimethylamino)ethyl)urea (BIOS-A-17) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that dimethylamine hydrochloride is used in this example instead of morpholine in Example 3, the preparation steps are the same as in Example 3. Obtain 40 mg of off-white solid (i.e., compound BIOS-A-17) (yield 39.07%). MS:437.2[M+H] + .

[0094] 1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.28(d,J=9.0Hz,2H),6.85(d,J=8.6Hz,2H),6.07(s,1H),4.37( s,1H),3.10~3.00(m,1H),2.45(t,J=6.1Hz,2H),2.24(s,6H),2.20~2.02(m,6H),1.84~1.55(m,10H).

[0095] Example 18: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(diethylamino)ethyl)urea (BIOS-A-18) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that in this example, diethylamine is used instead of morpholine in Example 3, the preparation steps are the same as in Example 3. Obtain 67mg of white solid (i.e., compound BIOS-A-18) (yield 60.72%). MS:389.2[M+H] + .

[0096] 1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.28(d,J=9.0Hz,2H),6.85(d,J=8.6Hz,2H),6.11(s,1H),4.39(s,1 H),3.13~3.02(m,1H),2.70(t,J=5.8Hz,2H),2.28~2.21(m,4H),2.20~2.02(m,12H),1.84~1.55(m,10H).

[0097] Example 19: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(ethylamino)ethyl)urea (BIOS-A-19) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-3 in Example 3, except that in this example, ethylamine hydrochloride is used instead of morpholine in Example 3, the preparation steps are the same as in Example 3. Obtain 76mg of white solid (i.e. compound BIOS-A-19) (yield 74.23%). MS:361.2[M+H] + .

[0098] 1 H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.29(d,J=8.9Hz,2H),6.88(d,J=8.9Hz,2H),5.93(t,J=4.7Hz,1H),4.37~4.33(m,1H),3.32(q, J=4.3Hz,2H), 2.89~2.82(m,2H),2.83~2.66(m,6H),1.98~1.92(m,4H),1.81~1.74(m,2H),1.77~1.49(m,6H),1.15(t,J=6.0Hz,3H).

[0099] Example 20: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-morpholinylethyl)thiourea (BIOS-A-20) [ka] The synthetic route is as follows: [ka] Compound BIOS-A-3 (100 mg, 0.248 mmol) and Lawesson Reagent (101 mg, 0.248 mmol) were dissolved in 4 mL of anhydrous 1,4-dioxane and reacted under reflux for 16 h. The reaction was detected by thin layer chromatography to confirm that the raw materials had completely reacted.

[0100] The reaction solution was concentrated to dryness and purified on a preparative plate (petroleum ether:ethyl acetate:triethylamine=5:4:1) to obtain 34 mg of a yellow solid (i.e., compound BIOS-A-20) (yield 32.75%).

[0101] MS:419.1[M+H] + .

[0102] 1 H NMR(400MHz,DMSO-d6)δ9.18(s,1H),7.25(d,J=9.0Hz,2H),7.17(t,J=3.8Hz,1H),6.81(d,J=9.0Hz,2H),4.37~4.32(m,1H),3.69~ 3.59(m,6H),2.83~2.77(m,1H),2.77~2.66(m,4H),2.59(t,J=5.7Hz,2H),2.52~2.46(m,4H),2.00~1.90(m,4H),1.81~1.49(m,6H).

[0103] The synthesis route and preparation method of compound BIOS-A-3 are described in Example 3, and are omitted here.

[0104] Example 21: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(piperidin-1-yl)ethyl)thiourea (BIOS-A-21) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-20 in Example 20, except that in this example, BIOS-A-4 is used instead of BIOS-A-3 in Example 20, the preparation steps are the same as in Example 20. Obtain 47mg of white solid (i.e. compound BIOS-A-21) (yield 45.49%).

[0105] MS:417.1[M+H] + .

[0106] 1 H NMR(400MHz,DMSO-d6)δ8.59(s,1H),7.27(d,J=8.9Hz,2H),6.81(d,J=8.9Hz,2H),6.13(s,1H),4.28~4.18(m,1H),3.25~3.15(m,2H),2.82~2.69(m ,1H),2.60(d,J=5.5Hz,2H),2.47~2.36(m,6H),2.08(t,J=5.4Hz,2H),2. 02~1.85(m,4H),1.85~1.73(m,2H),1.65~1.50(m,8H),1.45~1.34(m,2H).

[0107] The synthesis route and preparation method of compound BIOS-A-4 are described in Example 4, and are omitted here.

[0108] Example 22: Preparation of 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)thiourea (BIOS-A-22) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-20 in Example 20, except that in this example, BIOS-A-5 is used instead of BIOS-A-3 in Example 20, the preparation steps are the same as in Example 20. Obtain 22mg of white solid (i.e., compound BIOS-A-22) (yield 22.03%).

[0109] MS:403.1[M+H] + .

[0110] 1 H NMR(400MHz,DMSO-d6)δ8.47(s,1H),7.26(d,J=8.8Hz,2H),6.82(d,J=8.8Hz,2H),6.01(t,J=5.4Hz,1H),4.28~4.16(m, 1H), 3.21~3.14(m,2H),2.72~2.62(m,1H),2.61~2.52(m,2H),2.50~2.37(m,8H),2.05~1.91(m,4H),1.79~1.48(m,10H).

[0111] The synthesis route and preparation method of compound BIOS-A-5 are described in Example 5, and are omitted here.

[0112] Example 23: Preparation of (R)-1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(2-methylpyrrolidin-1-yl)ethyl)thiourea (BIOS-A-23) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-A-20 in Example 20, except that in this example, BIOS-A-6 is used instead of BIOS-A-3 in Example 20, the preparation steps are the same as in Example 20. Obtain 15mg of white solid (i.e. compound BIOS-A-23) (yield 14.52%).

[0113] MS:417.1[M+H]+ .

[0114] 1 H NMR(400MHz,DMSO-d6)δ8.58(s,1H),8.20(s,2H),7.29(d,J=8.6Hz,2H),6.77 (d,J=8.6Hz,2H),6.03(s,1H),4.21(s,1H),2.82(d,J=9.3Hz,2H),2.74(t,J= 7.8Hz,1H),2.61(s,2H),2.45(s,2H),2.21(d,J=9.0Hz,2H),2.14~2.04(m,2H ),2.02~1.86(m,4H),1.85~1.50(m,6H),1.40~1.30(m,1H),1.16~1.03(m,5H).

[0115] The synthesis route and preparation method of compound BIOS-A-6 are described in Example 6, and are omitted here.

[0116] Example 24: Histamine H3 receptor antagonist activity of compounds Using SUVN-G3031 as a positive control, 13 target compounds and one positive control compound were screened from the synthesized compounds by FLIPR measurement method (NIH assay guidance manual: HTS Assay Validation-Section 4.3. Analysis (Potency), https: / / www.ncbi.nlm.nih.gov / books / NBK83783), and their histamine H3 receptor antagonist activity was measured. The results are shown in Table 1.

[0117] Table 1: Histamine H3 receptor antagonist activity of compounds [Table 1] As can be seen from the receptor antagonist activity shown in Table 1, some compounds exhibited high histamine H3 receptor inhibitory activity, and most of the compounds were more active than the positive control compound SUVN-G3031 at 5 nM.

[0118] Example 25: Safety of Compound hERG In cardiac myocytes, inhibition of the delayed rectifier potassium current (IKr) channel protein encoded by the human Ether-a-go-go Related Gene (hERG) is the most important mechanism by which drugs cause QT interval prolongation. Due to its unique molecular structure, hERG can be inhibited by a variety of compounds with different structures, causing severe arrhythmias. Statistics show that 25-40% of lead compounds show some degree of hERG-related toxicity. Therefore, early evaluation of the effect on hERG is very important in the drug development process.

[0119] In a HEK293 cell line stably expressing the hERG ion channel, the inhibition rate of the compounds against the hERG channel was detected by manual patch clamp. The hERG inhibitor Cisapride (100 nM) was used as a control.

[0120] As shown in Table 2, the compounds BIOS-A-13 to BIOS-A-15, BIOS-A-3 to BIOS-A-5, BIOS-A-10, and BIOS-A-11 (10 μM) have an inhibition rate of less than 5% against the hERG channel. This indicates that the test compounds basically have no hERG inhibitory activity, that is, the test compounds have good safety.

[0121] Table 2. Inhibition rate of compounds against hERG channel [Table 2] Here, "-" means not measured.

[0122] Example 26: Pain model activity data of compound BIOS-A-3 For SD male rats weighing 180-200g, the sciatic nerve of the right hind leg was exposed, and four loops were loosely ligated with sterilized chrome catgut (No. 4, diameter 0.15 mm) in the area just before it branches off from the sciatic nerve, with 1-2 mm spacing between each loop, and the muscle and skin were sutured to construct a chronic constriction injury (CCI) model. In the sham-operated group (sham), the sciatic nerve was exposed, and the muscle and skin were sutured without ligation. Observations were made from 3 days after surgery, and on the 7th day, the mechanical sting pain threshold was measured for 2 consecutive days using an electronic algometer (ITC-2391).

[0123] CCI model rats with stable mechanical sting thresholds were randomly divided into three groups, namely, the model group, the pregabalin (Pre) group (30 mg / kg), and the BIOS-A-3 group (1 mg / kg), and administered orally at 1 mL / 100 g. The sham-operated group (sham) and the model group (model) were administered orally with the same volume of saline. The basal value was measured before administration, and the mechanical pain threshold was detected 0.5 hours, 1 hour, 2 hours, 4 hours, and 6 hours after a single administration. The p value was calculated using one-way ANOVA and T-test. The results are shown in Figure 1.

[0124] As a result, when compound BIOS-A-3 was administered at 1 mg / kg to the SD rat CCI neuropathic pain model, the mechanical pain threshold of the CCI model rats was significantly increased, and the mechanical tingling pain threshold was significantly different from the model group at 0.5 hours, 1 hour, and 6 hours after administration (P<0.05), and when pregabalin was administered at 30 mg / kg, the mechanical tingling pain threshold of the CCI rats increased only at 0.5 hours and 1 hour after administration, and was significantly different from the model group. This indicates that the duration of action of compound BIOS-A-3 is longer and superior to pregabalin. It also indicates that over time, compound BIOS-A-3 has a better effect on the mechanical tingling pain threshold than pregabalin at a single time point.

Claims

1. A phenylurea derivative, characterized in that it is a compound having the following structural formula I or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 wherein X is selected from O or S; m is selected from 0, 1, 2, 3, 4, 5 or 6; A is C １－６ is one selected from an alkyl group, -NR'R'', a substituted or unsubstituted 5-8 membered heterocyclic group, and a substituted or unsubstituted 5-8 membered heteroaryl group, and the heterocyclic group and heteroaryl group have at least one substituent, and the substituent is １－６ Alkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, halogen, amino group, hydroxyl group, cyano group, amide group, sulfone group, sulfoxide group, C １－６ Halogenated alkyl group, C １－６ Alkyl hydroxyl group, C １－６ Alkylamino group, C １－６ Alkylamide group, C １－６ Alkyl sulfone group, C １－６ Alkyl sulfoxide group, C １－６ Halogenated alkoxy group, C １－６ Alkoxyhydroxyl group, C １－６ Alkoxyamino group, C １－６ Alkoxyamide group, C １－６ Alkoxysulfonic acid group, C １－６ one or more selected from an alkoxysulfoxide group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, and a heteroaryl group; R′ and R″ are each independently hydrogen, C １－６ Alkyl group, C １－６ Alkoxy group, halogen, amino group, hydroxyl group, carboxyl group, carbonyl group, amide group, cyano group, C １－６ Halogenated alkyl group, C １－６ Alkyl hydroxyl group, C １－６ Alkylamino group, C １－６ Alkylamide group, C １－６ Halogenated alkoxy group, C １－６ Alkoxyhydroxyl group, C １－６ Alkoxyamino group, C １－６ one or more selected from alkoxyamide groups, and R′ and R″ cannot simultaneously be hydrogen; R １ , R ２ are each independently hydrogen, C １－６ is selected from an alkyl group, a -C(O)-alkyl group or a -S(O)2-alkyl group; R ３ , R ４ , R ５ , R ６ are each independently hydrogen, halogen, or C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, amino group, hydroxyl group, cyano group, amide group, sulfone group, sulfoxide group, C １－６ Halogenated alkyl group, C １－６ Alkyl hydroxyl group, C １－６ Alkylamino group, C １－６ Alkylamide group, C １－６ Alkyl sulfone group, C １－６ alkyl sulfoxide groups, Or, R ３ , R ４ together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring system, said benzobicyclic ring system including, but not limited to, a benzoheterocycle; Or, R ５ , R ６ together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring system, said benzobicyclic ring system including, but not limited to, a benzoheterocycle; The heterocyclic group, heteroaryl group, and benzoheterocycle contain at least one heteroatom, and the heteroatom is selected from N, O, or S.

2. The phenylurea derivative according to claim 1, characterized in that it is a compound having the following structural formula II or a pharma- ceutically acceptable salt thereof: 【Chemistry 2】 wherein X is selected from O or S; m is selected from 0, 1, 2, 3, 4, 5 or 6; A is one selected from a substituted or unsubstituted 5-8 membered heterocyclic group and a substituted or unsubstituted 5-8 membered heteroaryl group, and the heterocyclic group and the heteroaryl group have at least one substituent, and the substituent is C １－６ Alkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, halogen, amino group, hydroxyl group, cyano group, amide group, sulfone group, sulfoxide group, C １－６ Halogenated alkyl group, C １－６ Alkyl hydroxyl group, C １－６ Alkylamino group, C １－６ Alkylamide group, C １－６ Alkyl sulfone group, C １－６ Alkyl sulfoxide group, C １－６ Halogenated alkoxy group, C １－６ Alkoxyhydroxyl group, C １－６ Alkoxyamino group, C １－６ Alkoxyamide group, C １－６ Alkoxysulfonic acid group, C １－６ one or more selected from an alkoxysulfoxide group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, and a heteroaryl group; R ３ , R ４ , R ５ , R ６ are each independently hydrogen, halogen, or C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, amino group, hydroxyl group, cyano group, amide group, sulfone group, sulfoxide group, C １－６ Halogenated alkyl group, C １－６ Alkyl hydroxyl group, C １－６ Alkylamino group, C １－６ Alkylamide group, C １－６ Alkyl sulfone group, C １－６ alkyl sulfoxide groups, Or, R ３ , R ４ together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring system, said benzobicyclic ring system including, but not limited to, a benzoheterocycle; Or, R ５ , R ６ together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring system, said benzobicyclic ring system including, but not limited to, a benzoheterocycle; The heterocyclic group, heteroaryl group, and benzoheterocycle contain at least one heteroatom, and the heteroatom is selected from N, O, or S.

3. The phenylurea derivative according to claim 2, which is a compound having the following structural formula II-1 or a pharma- ceutically acceptable salt thereof: 【Chemistry 3】 wherein m is selected from 1, 2, 3, 4, 5 or 6; A is one selected from a substituted or unsubstituted 6-membered heterocyclic group and a substituted or unsubstituted 6-membered heteroaryl group, and the heterocyclic group and the heteroaryl group have at least one substituent, and the substituent is C １－６ Alkyl group, C １－６ Alkoxy group, halogen, amino group, hydroxyl group, C １－６ Halogenated alkyl group, C １－６ Alkyl hydroxyl group, C １－６ Alkylamino group, C １－６ Halogenated alkoxy group, C １－６ Alkoxyhydroxyl group, C １－６ one or more selected from alkoxyamino groups, R ３ , R ４ , R ５ , R ６ are each independently hydrogen, halogen, or C １－６ Alkyl group, amino group, hydroxyl group, C １－６ Halogenated alkyl group, C １－６ Alkyl hydroxyl group, C １－６ alkylamino groups, The heterocyclic group and the heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O, and S.

4. The phenylurea derivative according to claim 1, characterized in that it is a compound having the following structural formula III or a pharma- ceutically acceptable salt thereof: 【Chemistry 4】 wherein m is selected from 1, 2, 3, 4, 5 or 6; R′ and R″ are each independently hydrogen, C １－６ Alkyl group, C １－６ Alkoxy group, halogen, amino group, hydroxyl group, carboxyl group, carbonyl group, amide group, cyano group, C １－６ Halogenated alkyl group, C １－６ Alkyl hydroxyl group, C １－６ Alkylamino group, C １－６ Alkylamide group, C １－６ Halogenated alkoxy group, C １－６ Alkoxyhydroxyl group, C １－６ Alkoxyamino group, C １－６ one or more selected from alkoxyamide groups, and R′ and R″ cannot simultaneously be hydrogen; R ３ , R ４ , R ５ , R ６ are each independently hydrogen, halogen, or C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, amino group, hydroxyl group, cyano group, amide group, sulfone group, sulfoxide group, C １－６ Halogenated alkyl group, C １－６ Alkyl hydroxyl group, C １－６ Alkylamino group, C １－６ Alkylamide group, C １－６ Alkyl sulfone group, C １－６ alkyl sulfoxide groups, Or, R ３ , R ４ together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring system, said benzobicyclic ring system including, but not limited to, a benzoheterocycle; Or, R ５ , R ６ together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring system, said benzobicyclic ring system including, but not limited to, a benzoheterocycle; The benzoheterocycle contains at least one heteroatom, the heteroatom being selected from N, O or S.

5. The phenylurea derivative according to claim 1, characterized in that it is a compound having the following structural formula IV or a pharma- ceutically acceptable salt thereof: 【Chemistry 5】 (Wherein, A is C １－６ alkyl groups, R ３ , R ４ , R ５ , R ６ are each independently hydrogen, halogen, or C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, amino group, hydroxyl group, cyano group, amide group, sulfone group, sulfoxide group, C １－６ Halogenated alkyl group, C １－６ Alkyl hydroxyl group, C １－６ Alkylamino group, C １－６ Alkylamide group, C １－６ Alkyl sulfone group, C １－６ alkyl sulfoxide groups, Or, R ３ , R ４ together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring system, said benzobicyclic ring system including, but not limited to, a benzoheterocycle; Or, R ５ , R ６ together with the carbon atoms on the benzene ring to which they are respectively attached form a substituted or unsubstituted benzobicyclic ring system, said benzobicyclic ring system including, but not limited to, a benzoheterocycle; The benzoheterocycle contains at least one heteroatom, the heteroatom being selected from N, O or S.

6. 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-cyclopentyl urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-cyclohexylurea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-morpholinylethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(piperidin-1-yl)ethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(2-methylpyrrolidin-1-yl)ethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(4,4-difluoropiperidin-1-yl)ethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(thiomorpholinylethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(4-hydroxypiperidin-1-yl)ethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(4-isopropylpiperazin-1-yl)ethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(3-hydroxypiperidin-1-yl)ethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(N-methylhomopiperazin-1-yl)ethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(piperazin-1-yl)ethyl)urea, 1-(2-(4-cyclobutylpiperazin-1-yl)ethyl)-3-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-isopropylurea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(dimethylamino)ethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(diethylamino)ethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(ethylamino)ethyl)urea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-morpholinylethyl)thiourea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(piperidin-1-yl)ethyl)thiourea, 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)thiourea, or 1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(2-methylpyrrolidin-1-yl)ethyl)thiourea 1. A phenylurea derivative, characterized in that it is a compound, an isomer, a solvate, or a pharma- ceutically acceptable salt thereof having the structure:

7. (R)-1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(2-methylpyrrolidin-1-yl)ethyl)urea, or (R)-1-(4-((1-cyclobutylpiperidin-4-yl)oxy)phenyl)-3-(2-(2-methylpyrrolidin-1-yl)ethyl)thiourea A phenylurea derivative characterized in that it is a compound having the structure:

8. A pharmaceutical composition comprising an active ingredient according to any one of claims 1 to 7 and at least one pharma- ceutically acceptable carrier or excipient.

9. 10. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 in the preparation of a medicament for the prevention or treatment of a disease associated with the histamine H3 receptor.

10. The use according to claim 9, characterized in that the pharmaceutical composition is used for the prevention or treatment of cognitive impairment, dementia, attention deficit hyperactivity disorder, schizophrenia, epilepsy, sleep disorders, sleep apnea syndrome, obesity, eating disorders, pain and pruritus.

11. The use according to claim 9, characterized in that the pharmaceutical composition is used for the prevention or treatment of neuropathic pain, including but not limited to peripheral neuropathic pain or central neuropathic pain.

Images