Histamine H3 receptor inhibitors and their use in medicine

Abstract

The present invention relates to a novel histamine H3 receptor inhibitor, specifically to the structural forms of the compounds, such as free base, isomers, solvates, and pharma- ceutically acceptable salt forms, the method for preparing the compounds, the compositions containing the compounds, and the therapeutic use thereof.The present invention is based on the histamine H3 receptor ligand, and has developed a series of compounds with novel structures, and has carried out a series of related biological experiments on the compounds.The test results all 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 relates to histamine H3 receptor inhibitors and their use in medicine, in particular to 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 object of the present invention is to provide a histamine H3 receptor inhibitor having a novel structure, which can be used 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 histamine H3 receptor inhibitor which is a compound having the following structural formula I or a pharma- ceutically acceptable salt thereof. [ka] In the formula, W is -(CH2) m -or-NR6(CH2) m - selected from X is selected from O or S; n0, n1 are selected from 1, 2 or 3, and m is selected from 0, 1, 2, 3, 4, 5 or 6; R0 is -NR'R'', -O(CH2) m is one selected from the group consisting of NR'R'', a substituted or unsubstituted 5-8 membered heterocyclic group, and a substituted or unsubstituted 5-8 membered heteroaryl group, and the substituents on the heterocyclic group and the heteroaryl group are each 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, C1-6 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, 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 R6 are each independently hydrogen or C 1-6 -alkyl group, -C(O)-alkyl group or -S(O)-alkyl group, R2, R3, R4, and R5 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 R2 and R3 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 R4 and R5 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; R7 and R8 are each independently hydrogen, halogen, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, amino 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 Halogenated alkoxy groups, C 1-6 Alkoxyhydroxyl group, C 1-6 Alkoxyamino group, C 1-6 Alkoxyamide group, C 1-6 Alkoxysulfonic acid group, C 1-6 alkoxy sulfoxide groups, Alternatively, R7 and R8 form a ring with the nitrogen atom to which they are bonded, and the substituents on the ring are hydrogen, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy 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 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 8-membered heterocyclic group, and a 3- to 8-membered heteroaryl group; The heterocyclic, heteroaryl and benzoheterocycle groups contain at least one heteroatom, which is selected from N, O or S.

[0010] Preferably, the histamine H3 receptor inhibitor 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; n0, n1 are selected from 1, 2 or 3, and m is selected from 0, 1, 2, 3, 4, 5 or 6; R0 is -NR'R'', -O(CH2) m is one selected from the group consisting of NR′R″, a substituted or unsubstituted 5-8 membered heterocyclic group, and a substituted or unsubstituted 5-8 membered heteroaryl group, and the substituent on the heterocyclic group or heteroaryl group 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 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, 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 is hydrogen, C 1-6 -alkyl group, -C(O)-alkyl group or -S(O)-alkyl group, R2, R3, R4, and R5 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 R2 and R3 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 R4 and R5 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 histamine H3 receptor inhibitor is a compound having the following structural formula II-1 or a pharma- ceutically acceptable salt thereof. [ka] wherein X is selected from O or S; m is selected from 1 or 2; R0 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 substituent on the heterocyclic group or heteroaryl group 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 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, 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; R1 is hydrogen, C 1-6 -alkyl group, -C(O)-alkyl group or -S(O)-alkyl group, R2, R3, R4, and R5 are each independently hydrogen, halogen, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C2-6 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, The heterocyclic and heteroaryl groups contain at least one heteroatom, which is selected from N, O or S.

[0012] Preferably, the histamine H3 receptor inhibitor is a compound having the following structural formula II-2 or a pharma- ceutically acceptable salt thereof. [ka] wherein m is selected from 1 or 2; R0 is -NR'R'', -O(CH2) m One selected from NR'R''; 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 is hydrogen, C 1-6 -alkyl group, -C(O)-alkyl group or -S(O)-alkyl group, R2, R3, R4, and R5 are each independently hydrogen, halogen, or C1-6 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.

[0013] Preferably, the histamine H3 receptor inhibitor is a compound having the following structural formula III: or a pharma- ceutically acceptable salt thereof. [ka] wherein X is selected from O or S; n0, n1 are selected from 1, 2 or 3, and m is selected from 0, 1, 2, 3, 4, 5 or 6; R0 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 substituent on the heterocyclic group or heteroaryl group 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 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, C 1-6one 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; R1 and R6 are each independently hydrogen or C 1-6 -alkyl group, -C(O)-alkyl group or -S(O)-alkyl group, R2, 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 R2 and R3 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 R4 and R5 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.

[0014] Preferably, the histamine H3 receptor inhibitor is a compound having the following structural formula III-1 or a pharma- ceutically acceptable salt thereof. [ka] In the formula, n0 and n1 are selected from 1, 2, or 3, and m is selected from 0, 1, 2, 3, 4, 5, or 6; R0 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 substituent on the heterocyclic group or heteroaryl group 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, 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 an alkoxyamino group and a 3- to 6-membered cycloalkyl group; R2, 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.

[0015] The present invention relates to histamine H3 receptor inhibitors, including compounds having the following structures, isomers, solvates, or pharma- ceutically acceptable salts thereof, numbered BIOS-B-1 to BIOS-B-31. BIOS-B-1: 2-morpholine-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-2: (R)-2-(2-methylpyrrolidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-3: 2-(piperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-4: 2-(N-methylhomopiperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-5: 2-(4,4-difluoropiperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-6: 2-(4-hydroxypiperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-7: 2-(thiomorpholin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-8: 2-(2-(2-hydroxyethyl)piperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-9: 2-(piperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-10: 2-(4-methylpiperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-11: 2-(3-hydroxypiperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-12: 2-(4-cyclobutylpiperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-13: 1-(2-morpholinoethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea; BIOS-B-14: (R)-1-(2-(2-methylpyrrolidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea; BIOS-B-15: 1-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)-3-(2-(piperidin-1-yl)ethyl)urea; BIOS-B-16: 1-(2-(piperazin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea; BIOS-B-17: 1-(2-(N-methylhomopiperazin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea; BIOS-B-18: 1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea; BIOS-B-19: 1-(2-(4-hydroxypiperidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea; BIOS-B-20: 1-(2-(thiomorpholin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea; BIOS-B-21: 1-(2-(2-hydroxyethyl)piperidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea; BIOS-B-22: 1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea; BIOS-B-23: 1-(2-(3-hydroxypiperidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea; BIOS-B-24: 1-(2-(4-cyclobutylpiperazin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea; BIOS-B-25: 2-morpholinyl-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide; BIOS-B-26: (R)-2-(2-methylpyrrolidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide; BIOS-B-27: 2-piperidinyl-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide; BIOS-B-28: 2-(N-methylhomopiperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide; BIOS-B-29: 2-(diethylamino)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-30: 2-(dimethylamino)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide; BIOS-B-31: 2-(2-(dimethylamino)ethoxy)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide.

[0016] The structural formulae of the compounds numbered BIOS-B-1 to BIOS-B-31 above or pharma- ceutically acceptable salts thereof are as follows: [ka]

[0017] The present invention further provides a histamine H3 receptor inhibitor comprising a chiral compound having the structure: or a pharma- ceutically acceptable salt thereof. (R)-2-(2-methylpyrrolidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, (R)-1-(2-(2-methylpyrrolidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea, or (R)-2-(2-methylpyrrolidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide.

[0018] 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).

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] The term "alkyl group" means 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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. Synthesis method 1: Applied to compounds of formula II, where X=O, R1=H, and R0=NR'R''. [ka] The reaction process is as follows: p-Fluoronitrobenzene compound (raw material 1) and sodium hydride were dissolved in N,N-dimethylformamide, reacted, and then reacted in trifluoroacetic acid solution to obtain intermediate 2. Intermediate 2 was then reacted with p-toluenesulfonyl chloride to obtain intermediate 3. Intermediate 3 and piperidine were reacted with S N 2 reacted to obtain intermediate 4, which was then reduced to intermediate 5 under the catalysis of Fe powder using ammonium chloride as the hydrogen source. Intermediate 5 was acylated with haloalkyl acid chloride to obtain intermediate 6. Finally, intermediate 6 was subjected to a substitution reaction with an amine to obtain intermediate 7 or the target compound.

[0030] The synthesis method of intermediate 1 is as follows. [ka]

[0031] Synthesis method 2: Applied to compounds of formula III, where X=O, R1=H, R6=H, and R0=NR'R''. The reaction pathway is as follows: [ka] The reaction process is as follows: Intermediate 5 was reacted with a chloroalkyl isocyanate to give intermediate 8, which was then subjected to a substitution reaction with an amine to give the target compound.

[0032] Synthesis method 3: Applied to compounds of formula II, where X=S, R1=H, and R0=NR'R''. The reaction pathway is as follows: [ka] The reaction process is as follows: Intermediate 7 was reacted with Lawesson's reagent to give the target compound.

[0033] The substituents R', R'', R1, R2, R3, R4 and R5 in the above-mentioned synthesis methods 1, 2 and 3 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 1-6The alkoxyamide group is one or more groups selected from the group consisting of alkoxyamide groups, and R' and R'' cannot simultaneously be hydrogen. R2, R3, R4, and R5 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, R2 and R3 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 benzoheterocycles. Alternatively, R4 and R5 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] The present invention provides the use of said compound or said pharmaceutical composition for preventing or treating a disease associated with the histamine H3 receptor.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] Compared with the prior art, the present invention has the following beneficial effects: Based on histamine H3 receptor ligand, the present invention has developed a series of histamine H3 receptor inhibitors with novel structure. The compounds have simple synthesis route and easy availability of raw materials. In addition, a series of related 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]

[0043] [Figure 1] FIG. 1 shows the change in mechanical tingle pain threshold for each experimental group at different times and different doses. [Diagram 2] FIG. 2 shows the changes in mechanical tingle pain thresholds for each experimental group at different times.

[0044] 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. In Figure 2, 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

[0045] 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.

[0046] 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

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 1. Preparation of starting compound 2 The raw material compound 2 used in the preparation process of the common intermediate B1 was prepared in-house, and the synthetic route is as follows: [ka]

[0051] 3-(benzyloxy)cyclobutanone (5.0g, 28.37mmol) and anhydrous methanol (34mL) were added to a 250mL eggplant flask, mixed uniformly, purged with nitrogen three times, cooled in an ice-water bath for 15min, sodium borohydride powder (717mg / time, 3 times, 56.75mmol all added within 0.5h) was added in several portions, and finally reacted at room temperature for 4~5h. Thin layer chromatography detected that the raw material was essentially completely reacted. The reaction solution was quenched by adding saline (1.0mL), concentrated and dried, ethyl acetate was added and stirred, then phase separated, and the aqueous phase was extracted twice with ethyl acetate, and the organic phase was combined. The organic phase was washed with saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain 5.31g of a colorless oily liquid (i.e., compound 2) (yield 99%). MS: 179.1[M+H]+.

[0052] 1 H NMR(400MHz,DMSO-d6)δ7.38~7.26(m,5H),4.48(s,2H),4.04(t,J=5.6Hz,1H), 3.92~3.79(m,1H),3.80(d,J=4.4Hz,1H),2.35~2.30(m,2H),2.03~1.99(m,2H).

[0053] 2. Preparation of common intermediate B1 The synthetic route of intermediate B1 is as follows. [ka]

[0054] Step 1: Synthesis of 3-(4-nitrophenoxy)cyclobutanol (3) Compound 2 (2.155 g, 12.09 mmol) was dissolved in 15 mL of anhydrous N,N-dimethylformamide and cooled in an ice-water bath for 5 min. Sodium hydride (580 mg, 14.51 mmol) was added under nitrogen protection and reacted for 0.5-1 h in an ice-water bath. A solution of p-fluoronitrobenzene (compound 1, 1.54 g) and 5 mL of anhydrous N,N-dimethylformamide was slowly added dropwise within 15 min and reacted at room temperature for 5-6 h. Thin layer chromatography detected that the raw material had essentially reacted completely. The reaction solution was quenched by putting it into 200 mL of ice water, extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, and concentrated and dried to obtain 3.89 g of a yellow crude product (yield 99%).

[0055] The yellow crude product (3.89 g) was dissolved in 40 mL of trifluoroacetic acid and refluxed in an oil bath for 3 to 4 h. Thin layer chromatography confirmed that the raw materials had essentially reacted completely. The reaction solution was then cooled to 0 °C in an ice-water bath. o The mixture was cooled to 30°C and sodium carbonate solution was added dropwise until the pH was neutral. The mixture was extracted with ethyl acetate (70 mL x 3), the organic phases were combined, the organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 4.4 g of a yellow crude product. The mixture was purified by flash column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain 1.358 g of a yellow powder (i.e., compound 3) (yield 53.7%). MS:210.1[M+H] + .

[0056] 1 H NMR(400MHz,DMSO-d6)δ8.19(d,J=9.2Hz,2H),7.05(d,J=9.2Hz,2H), 5.26 (d,J=6.8Hz,1H),4.43(m,1H),3.87(m,1H),2.91~2.83(m,2H),2.01~1.87(m,2H).

[0057] Step 2: Synthesis of 3-(4-nitrophenoxy) 4-cyclobutyltoluenesulfonate (4) Compound 3 (4.64 g, 22.22 mmol), 9.2 mL of triethylamine, and p-toluenesulfonyl chloride (1.86 g, 33.33 mmol) were dissolved in 40 mL of anhydrous methylene chloride, and after nitrogen replacement, the mixture was reacted overnight in an oil bath at 30°C. Thin layer chromatography showed that the raw materials had essentially reacted completely.

[0058] Work-up: The reaction mixture was quenched by adding 20 mL of water, the phases were separated, and the aqueous phase was extracted with dichloromethane (50 mL x 3), and the organic phases were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product. Finally, the mixture was triturated with methyl-tert-butyl ether for 1-2 h to obtain 6.73 g (i.e., compound 4) as a white powder (yield 83.38%). MS:364.1[M+H] + .

[0059] 1 H NMR(400MHz,DMSO-d6)δ8.17(s,2H),7.82(d,J=9.0Hz,2H),7.50(d,J=9.0Hz,2H),7.00(d,J=7.8,2 H),4.62(t,J=7.0Hz,1H),4.50(t,J=7.0Hz,1H),2.94~2.87(m,2H),2.43(s,3H),2.22~2.15(m,2H).

[0060] Step 3: Synthesis of 1-(3-(4-nitrophenoxy)cyclobutyl)piperidine (5) Compound 4 (800 mg, 2.20 mmol) and 10 mL of piperidine were mixed and reacted overnight at 100° C. in an oil bath, and thin layer chromatography detected that the raw materials had essentially reacted completely.

[0061] Post-treatment: The reaction solution was cooled to room temperature, 20 mL of water was added and mixed uniformly, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 736 mg of a crude product (i.e., compound 5) (yield 99%). MS:277.1[M+H] +.

[0062] 1 H NMR(400MHz,DMSO-d6)δ8.28~8.14(d,2H),7.11~6.98(d,2H),4.90~4.85(m,1H ),2.91~2.86(m,1H),2.91~2.86(m,3H),2.28~2.14(m,5H),1.55~1.30(m,10H).

[0063] Step 4: Synthesis of 4-(3-(piperidin-1-yl)cyclobutoxy)aniline (6) Compound 5 (736 mg), reduced iron powder (862 mg, 7.0 eq.), and ammonium chloride (214 mg, 3.96 mmol) were dissolved in 6 mL of ethanol and 2 mL of aqueous solution, and reacted in an oil bath at 80 °C for 1 to 2 h. Thin layer chromatography detected that the raw materials were essentially completely reacted.

[0064] Work-up: The reaction solution was cooled to room temperature, filtered through diatomaceous earth, the filter cake was washed with a small amount of ethanol, the filtrate was concentrated to dryness, 10 mL of sodium bicarbonate solution was added, extracted with ethyl acetate (20 mL x 3), the organic phase was combined, the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 583 mg of a brown oily crude product (i.e., compound 6) (yield 99%). MS:347.2[M+H] + .

[0065] Step 5: Synthesis of 2-chloro-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (B1) Compound 6 (852 mg, 3.46 mmol) and triethylamine (961 μL, 6.92 mmol) were dissolved in 12 mL of anhydrous methylene chloride, 358 μL of chloroacetyl chloride was added in an ice-water bath, and the mixture was allowed to react at room temperature overnight (the reaction solution changed from yellowish brown to dark brown). Thin layer chromatography detected that the raw material had essentially reacted completely.

[0066] Post-treatment: The reaction mixture was quenched with 15 mL of sodium bicarbonate solution, extracted with dichloromethane (20 mL x 3), and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 1.42 g of a brown oily crude product. The product was purified by flash column chromatography (petroleum ether: ethyl acetate: triethylamine = 2: 1: 0.2) to obtain 720 mg of a pale yellow powder (i.e., compound B1) (yield 64.5%). MS:352.3[M+H] + .

[0067] 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),7.47(d,2H),6.78(d,2H),4.70~4.65( m,1H),4.21(s,2H),2.91~2.79(m,1H),2.37~2.05(m,8H),1.55~1.32(m,6H).

[0068] 3. Preparation of common intermediate B2 The synthetic route to intermediate B2 is as follows. [ka]

[0069] Compound 6 (1.896 g, 7.70 mmol) was dissolved in 30 mL of anhydrous methylene chloride, cooled by stirring in an ice-water bath for 15 min, and 788 μL of chloroethyl isocyanate was added at low temperature and reacted at room temperature for 5 to 6 h (a large amount of white precipitate was precipitated from the reaction solution). Thin layer chromatography detected that the raw material was essentially completely reacted.

[0070] Post-treatment: The reaction solution was filtered, and the filter cake was washed with a small amount of dichloromethane, and concentrated and dried to obtain 1.894 g of a white powder (ie, compound B2) (yield 73.3%). MS:352.3[M+H] + .

[0071] 1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.26(d,J=9.0Hz,2H),6.69(d,J=9.0Hz,2H),6.28(t,J=5.8Hz,1H),4.66 ~4.61(m,1H),3.64(t,J=6.2Hz,2H),3.40(q,J=6.2Hz,2H),2.85(s,1H),2.40~1.98(m,8H),1.60~1.25(m,6H).

[0072] The following Examples 1 to 31 are preparation examples of the free radical and / or hydrochloride structure of the BIOS-B compounds of the present invention. In addition to the hydrochloride form described in the Examples, the BIOS-B 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 31 of the present invention.

[0073] Example 1: Synthesis of 2-morpholine-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-1) [ka] The synthetic route is as follows: [ka] Intermediate B1 (100 mg, 0.310 mmol), morpholine (81 μL, 0.929 mmol), and 323 μL of triethylamine were dissolved in 4 mL of acetonitrile and reacted overnight at 80° C. in an oil bath, and thin layer chromatography detected that the raw materials had essentially reacted completely.

[0074] The reaction solution was concentrated to dryness and purified on a separation plate (petroleum ether:ethyl acetate:triethylamine=5:4:1) to obtain 81 mg of a light brown oily liquid (ie, compound BIOS-B-1) (yield 69.96%). Further, the mixture was stirred with hydrochloric acid-ethyl acetate for 1 to 2 hours and dried by rotation to obtain 86 mg of a hydrochloride white solid (ie, the hydrochloride of compound BIOS-B-1) (salt production yield 88.83%). MS:374.1[M+H] + .

[0075] 1 H NMR(400MHz,DMSO-d6)δ9.58(s,1H),7.50(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),4.69~4.64(m,1H),3.7 0~3.54(m,4H),3.08(s,2H),2.88~2.81(m,1H),2.50~2.46(m,4H),2.37~2.00(m,8H),1.60~1.35(m,6H).

[0076] Example 2: Synthesis of (R)-2-(2-methylpyrrolidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-2) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-1 in Example 1, except that in this example, (R)-2-methylpyrrolidine was used instead of morpholine in Example 1, the preparation steps were the same as in Example 1. Obtained 75 mg of yellow-brown oily liquid (i.e., compound BIOS-B-2) (yield 65.12%).

[0077] Further, the mixture was stirred with hydrochloric acid-ethyl acetate for 1 to 2 hours and then dried by rotation to obtain 71 mg of a pink hydrochloride solid (ie, the hydrochloride of compound BIOS-B-2) (salt production yield: 79.13%). MS:372.1[M+H] + .

[0078] 1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),7.50(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),4.69~4.64(m,1H),3.38(d,J=15.5Hz,1H),3.11~3.06(m,1H) ,2.95(d,J=15.5Hz,1H),2.88~2.81(m,1H),2.49~2.03(m,10H),1.97~1 .87(m,1H),1.81~1.60(m,2H),1.57~1.29(m,7H),1.06(d,J=6.1Hz,3H).

[0079] Example 3: Synthesis of 2-(piperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-3) [ka] The synthetic route is as follows: [ka] Intermediate B1 (100 mg, 0.310 mmol), piperidine (85 μL, 0.929 mmol) and 323 μL of triethylamine were dissolved in 4 mL of acetonitrile and reacted overnight at 80° C. in an oil bath, and thin layer chromatography detected that the raw materials had essentially reacted completely.

[0080] The reaction solution was spun dry and purified on a preparative plate (petroleum ether:ethyl acetate:triethylamine=5:4:1) to obtain 100 mg of a pale yellow solid (i.e., compound BIOS-B-3) (yield 86.82%). MS: 372.1[M+H] + .

[0081] 1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),7.50(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),4.70~4.65(m,1 H),3.02(s,2H),2.95~2.81(m,1H),2.44(t,J=5.3Hz,4H),2.38~2.03(m,8H),1.66~1.31(m,12H).

[0082] Example 4: Synthesis of 2-(N-methylhomopiperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-4) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-1 in Example 1, except that in this example, N-methylhomopiperazine is used instead of morpholine in Example 1, the preparation steps are the same as in Example 1. Obtain 92mg of yellow solid (i.e., compound BIOS-B-4) (yield 74.09%).

[0083] Further, the mixture was stirred with hydrochloric acid-ethyl acetate for 1 to 2 hours and then dried by rotation to obtain 76 mg of a pale yellow hydrochloride solid (ie, the hydrochloride of compound BIOS-B-4) (salt production yield 64.89%). MS:401.1[M+H] + .

[0084] 1 H NMR(400MHz,DMSO-d6)δ9.53(s,1H),7.50(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),4.70~4.64(m,1H),3.23(s,2H),2.87~2.8 3(m,1H),2.80~2.71(m,4H),2.64~2.56(m,4H),2.38~2.14(m,9H),2.12~2.06(m,2H),1.83~1.71(m,2H),1.56~1.32(m,6H).

[0085] Example 5: Synthesis of 2-(4,4-difluoropiperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-5) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-3 in Example 3, except that in this example, 4,4-difluoropiperidine is used instead of piperidine in Example 3, the preparation steps are the same as in Example 3. Obtain 61mg of light yellow solid (i.e. compound BIOS-B-5) (yield 69.66%). MS:408.1[M+H] + .

[0086] 1 H NMR(400MHz,DMSO-d6)δ9.59(s,1H),7.51(d,J=9.0Hz,1H),6.75(d,J=9.0Hz,2H),4.70~4.65( m,1H),3.17(s,2H),2.87(s,1H),2.64(t,J=5.6Hz,4H),2.40~1.95(m,12H),1.57~1.31(m,6H).

[0087] Example 6: Synthesis of 2-(4-hydroxypiperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-6) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-1 in Example 1, except that in this example, 4-hydroxypiperidine is used instead of morpholine in Example 1, the preparation steps are the same as in Example 1. Obtain 94mg of yellow solid (i.e., compound BIOS-B-6) (yield 78.25%).

[0088] Further, the mixture was stirred with hydrochloric acid-ethyl acetate for 1 to 2 hours and then dried by rotation to obtain 99 mg of a white hydrochloride solid (ie, the hydrochloride of compound BIOS-B-6) (salt production yield 88.64%). MS: 388.1[M+H] + .

[0089] 1 H NMR(400MHz,DMSO-d6)δ9.51(s,1H),7.50(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),4.70~4.65(m,1H),4.58(d,J=4.0Hz,1H) ,3.50~3.45(m,1H),3.04(s,2H),2.91(s,1H),2.76~2.71(m,2H),2.40~2.03(m,10H),1.80~1.68(m,2H),1.60~1.32(m,8H).

[0090] Example 7: Synthesis of 2-(thiomorpholin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-7) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-3 in Example 3, except that in this example, thiomorpholine is used instead of piperidine in Example 3, the preparation steps are the same as in Example 3. Obtain 86mg of light yellow solid (i.e., compound BIOS-B-7) (yield 71.21%). MS: 390.0[M+H] + .

[0091] 1 H NMR(400MHz,DMSO-d6)δ9.51(s,1H),7.51(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),4.70~4.65(m,1H), 3.10(s,2H),2.87(s,1H),2.77~2.74(m,4H),2.73~2.63(m,4H),2.40~2.04(m,8H),1.61~1.32(m,6H).

[0092] Example 8: Synthesis of 2-(2-(2-hydroxyethyl)piperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-8) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-1 in Example 1, except that in this example, 2-piperidineethanol is used instead of morpholine in Example 1, the preparation steps are the same as in Example 1. Obtain 105mg of colorless oily liquid (i.e., compound BIOS-B-8) (yield 81.50%).

[0093] Further, the mixture was stirred with hydrochloric acid-ethyl acetate for 1 to 2 hours and then dried by rotation to obtain 101 mg of a white hydrochloride solid (ie, the hydrochloride of compound BIOS-B-8) (salt production yield 81.83%). MS:416.1[M+H] + .

[0094] 1H NMR(400MHz,DMSO-d6)δ9.53(s,1H),7.50(d,J=9.1Hz,1H),6.76(d,J=9.1Hz,2H),4.70~4.65(m,1H),4.46(s,1H),3.57~3.38(m,2H),3.2 6(d,J=16.4Hz,1H),3.05(d,J=16.4Hz,1H),2.93~2.70(m,2H),2.59~2.55(m,1H),2.46~2.16(m,7H),2.13~2.08(m,2H),1.77~1.62(m,3H) H),1.54~1.45(m,7H),1.44~1.26(m,4H).

[0095] Example 9: Synthesis of 2-(piperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-9) [ka] The synthetic route is as follows: [ka] Intermediate B1 (150 mg, 0.465 mmol), 1-Boc-piperazine (260 mg, 1.394 mmol), and 323 μL of triethylamine were dissolved in 4 mL of acetonitrile and reacted overnight at 80° C. in an oil bath, and thin layer chromatography detected that the raw materials had essentially reacted completely.

[0096] The reaction solution was dried by spin drying and purified by a separation plate (petroleum ether: ethyl acetate: triethylamine = 5: 4: 1) to obtain 179 mg of an off-white solid intermediate. 105 mg of the intermediate was stirred in hydrochloric acid-ethyl acetate for 1-2 hours and spin dried to obtain 105 mg of a white hydrochloride solid (i.e., the hydrochloride of compound BIOS-B-9) (two-step yield 79.89%). MS:373.1[M+H] + .

[0097] 1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),10.72(s,1H),9.82(s,2H),7.56(d,J=9.0Hz,2H),6.83(d,J=9.0Hz,2H),4.92~4.87(m,1H),4.10(s,2 H),3.83(d,J=7.9Hz,1H),3.58~3.32(m,8H),2.96~2.89(m,2H),2.73~ 2.64(m,2H),2.40~2.29(m,2H),1.94~1.65(m,5H),1.40~1.30(m,1H).

[0098] Example 10: Synthesis of 2-(4-methylpiperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-10) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-3 in Example 3, except that in this example, 4-methylpiperazine is used instead of piperidine in Example 3, the preparation steps are the same as in Example 3. Obtain 107mg of light yellow solid (i.e., compound BIOS-B-10) (yield 89.30%). MS:373.1[M+H] + .

[0099] 1 H NMR(400MHz,DMSO-d6)δ9.51(s,1H),7.49(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),4.70~4.65(m,1H),3. 06(s,2H),2.86(d,J=7.8Hz,1H),2.42~2.20(m,14H),2.18(s,3H),2.13~2.07(m,2H),1.55~1.32(m,6H).

[0100] Example 11: Synthesis of 2-(3-hydroxypiperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-11) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-1 in Example 1, except that in this example, 3-hydroxypiperidine is used instead of morpholine in Example 1, the preparation steps are the same as in Example 1. Obtain 108mg of brown oily liquid (i.e., compound BIOS-B-11) (yield 89.90%).

[0101] Further, the mixture was stirred with hydrochloric acid-ethyl acetate for 1 to 2 hours and then dried by rotation to obtain 108 mg of a white hydrochloride solid (ie, the hydrochloride of compound BIOS-B-11) (salt production yield 84.16%). MS:388.1[M+H] + .

[0102] 1 H NMR(400MHz,DMSO-d6)δ9.54(s,1H),7.50(d,J=9.0Hz,2H),6.76(d,J=9.0Hz,2H),4.82~4.53(m,2H),3.63~3.57(m,1H),3.05(d,J=1.7Hz,2H) ),2.93~2.81(m,1H),2.73(d,J=10.7,1H),2.57(d,J=10.7,1H),2.39~ 2.02(m,10H),1.72~1.69(m,2H),1.57~1.34(m,7H),1.30~1.09(m,1H).

[0103] Example 12: Synthesis of 2-(4-cyclobutylpiperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-12) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-3 in Example 3, except that in this example, 4-cyclobutylpiperazine is used instead of piperidine in Example 3, the preparation steps are the same as in Example 3. Obtain 50mg of light yellow solid (i.e., compound BIOS-B-12) (yield 37.81%). MS: 427.3[M+H] + .

[0104] 1 H NMR(400MHz,DMSO-d6)δ9.52(s,1H),7.50(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),4.69(s,1H),3.07(s,2H),2.95(s,1H),2.74(s,1H),2 .45~2.04(m,12H),2.02~1.87(m,2H),1.78(t,J=9.0Hz,2H),1.70~1.58(m,2H),1.58~1.31(m,7H),1.29~1.20(m,1H),1.16~0.80(m,2H).

[0105] Example 13: Synthesis of 1-(2-morpholinoethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea (BIOS-B-13) [ka] The synthetic route is as follows: [ka] Intermediate B2 (100 mg, 0.284 mmol), morpholine (75 μL, 0.853 mmol), and 200 μL of triethylamine were dissolved in 4 mL of acetonitrile and reacted overnight at 80° C. in an oil bath, and thin layer chromatography detected that the raw materials had essentially reacted completely.

[0106] The reaction solution was spun dry and purified on a preparative plate (ethyl acetate:triethylamine=4:1) to obtain 99 mg of a yellow solid (i.e., compound BIOS-B-13) (yield 86.60%). MS:403.1[M+H] + .

[0107] 1 H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.25(d,J=9.0Hz,2H),6.68(d,J=9.0Hz,2H),5.95(t,J=5.4Hz,1H),4.68~4.59(m,1H) ),3.59(t,J=4.7Hz,4H),3.25~3.15(m,2H),2.95~2.83(m,1H),2.42~2.21(m,12H),2.15~2.05(m,2H),1.55~1.32(m,6H).

[0108] Example 14: Synthesis of (R)-1-(2-(2-methylpyrrolidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea (BIOS-B-14) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-13 in Example 13, except that in this example, (R)-2-methylpyrrolidine is used instead of morpholine in Example 13, the preparation steps are the same as in Example 13. Obtain 45mg of white solid (i.e. compound BIOS-B-14) (yield 39.56%). MS:401.2[M+H] + .

[0109] 1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.25(d,J=8.4Hz,2H),6.68(d,J=8.4Hz,2H),5.94(s,1H),4.63(s,1H),3.09(s,2) H),2.84(s,2H),2.40~1.99(m,11H),1.96~1.82(m,1H),1.66(t,J=7.8Hz,2H),1.58~1.20(m,8H),1.04(d,J=4Hz,3H).

[0110] Example 15: Synthesis of 1-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)-3-(2-(piperidin-1-yl)ethyl)urea (BIOS-B-15) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-13 in Example 13, except that in this example piperidine is used instead of morpholine in Example 13, preparation steps are the same as in Example 13. Obtain 87mg of white solid (i.e. compound BIOS-B-15) (yield 76.48%). MS:401.1[M+H] + .

[0111] 1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.25(d,J=9.0Hz,2H),6.68(d,J=9.0Hz,2H),5.92(t,J=5.3Hz,1H),4.68 ~4.58(m,1H),3.17(q,J=6.0Hz,2H),2.86(s,1H),2.46~2.15(m,12H),2.14~2.03(m,2H),1.58~1.30(m,12H).

[0112] Example 16: Synthesis of 1-(2-(piperazin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea (BIOS-B-16) [ka] The synthetic route is as follows: [ka] Intermediate B2 (300 mg, 0.852 mmol), 1-Boc-piperazine (477 mg, 2.558 mmol), and 600 μL of triethylamine were dissolved in 4 mL of acetonitrile and reacted overnight at 80° C. in an oil bath, and thin layer chromatography detected that the raw materials had essentially reacted completely.

[0113] The reaction solution was dried by spin drying and purified by a separation plate (ethyl acetate: triethylamine = 4:1) to obtain 346 mg of an intermediate in the form of an off-white solid. 207 mg of the intermediate was stirred in hydrochloric acid-ethyl acetate for 1-2 hours and spin drying to obtain 219 mg of a white hydrochloride solid (i.e., the hydrochloride of compound BIOS-B-16) (two-step yield 50.31%). MS:402.1[M+H] + .

[0114] 1 H NMR(400MHz,DMSO-d6)δ11.35(s,1H),8.42(s,1H),7.27(d,J=9.0Hz,2H),6.69(d,J=9.0Hz,2H),5.95(t,J=5.5Hz, 1H), 4.68~4.59(m,1H),3.22~3.16(m,2H),2.86(s,1H),2.46~2.15(m,12H),2.14~2.03(m,2H),1.58~1.30(m,10H).

[0115] Example 17: Synthesis of 1-(2-(N-methylhomopiperazin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea (BIOS-B-17) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-13 in Example 13, except that in this example, N-methylhomopiperazine is used instead of morpholine in Example 13, the preparation steps are the same as in Example 13. Obtain 74mg of yellow solid (i.e. compound BIOS-B-17) (yield 60.65%). MS:430.2[M+H] + .

[0116] 1 H NMR(400MHz,DMSO-d6)δ8.88(s,1H),7.29(d,J=9.0Hz,2H),6.69(d,J=9.0Hz,2H), 6.43(t,J=5.3Hz,1H),4.70~4.64(m,1H),3.24~3.21(m,4H),3.18~3.13(m,5H),3. 05~3.03(m,2H),2.85(t,J=5.2Hz,2H),2.71(d,J=3.9Hz,5H),2.62~2.58(m,3H),2 .18(t,J=9.9Hz,2H),1.99~1.89(m,2H),1.64~1.39(m,6H),1.18(t,J=7.3Hz,1H).

[0117] Example 18: Synthesis of 1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea (BIOS-B-18) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-13 in Example 13, except that in this example, 4,4-difluoropiperidine is used instead of morpholine in Example 13, preparation steps are the same as in Example 13. Obtain 97mg of white solid (i.e. compound BIOS-B-18) (yield 78.24%). MS:437.1[M+H] + .

[0118] 1 H NMR(400MHz,DMSO-d6)δ8.36(s,1H),7.25(d,J=9.0Hz,2H),6.68(d,J=9.0Hz,2H),5.96(t,J=5.5Hz,1H),4.68~4.58(m,1H),3.18(q,J=6.1 Hz,2H),2.87(s,1H),2.58~2.51(m,4H),2.45(t,J=6.4Hz,2H),2.37~2.16(m,6H),2.14~2.03(m,2H),2.02~1.88(m,4H),1.56~1.33(m,6H).

[0119] Example 19: Synthesis of 1-(2-(4-hydroxypiperidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea (BIOS-B-19) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-13 in Example 13, except that in this example, 4-hydroxypiperidine is used instead of morpholine in Example 13, preparation steps are the same as in Example 13. Obtain 97mg of pink solid (i.e. compound BIOS-B-19) (yield 81.99%). MS:437.1[M+H] + .

[0120] 1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.25(d,J=8.4Hz,2H),6.68(d,J=8.4Hz,2H),5.93(t,J=5.4Hz,1H),4.69~4.59(m,1H),4.57(s,1H),3.45( s,1H),3.16(q,J=6.0Hz,2H),2.93~2.85(m,1H),2.81~2.64(m,2H),2.4 2~2.16(m,8H),2.14~1.94(m,4H),1.81~1.62(m,2H),1.56~1.29(m,8H).

[0121] Example 20: Synthesis of 1-(2-(thiomorpholin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea (BIOS-B-20) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-13 in Example 13, except that in this example, thiomorpholine is used instead of morpholine in Example 13, preparation steps are the same as in Example 13. Obtain 103mg of yellow solid (i.e. compound BIOS-B-20) (yield 86.64%). MS:419.1[M+H] + .

[0122] 1 H NMR(400MHz,DMSO-d6)δ8.36(s,1H),7.25(d,J=9.0Hz,2H),6.68(d,J=9.0Hz,1H),5.91(t,J=5.4Hz,1H),4.68~4.58(m,1H),3.17(q, J=6.1Hz,2H),2.92~2.80(m,1H),2.72~2.57(m,8H),2.40(t,J=6.4Hz,2H),2.35~2.16(m,6H),2.14~2.03(m,2H),1.54~1.32(m,6H).

[0123] Example 21: Synthesis of 1-(2-(2-hydroxyethyl)piperidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea (BIOS-B-21) [ka] The synthetic route for the compound is as follows. [ka] Refer to the synthesis method of compound BIOS-B-13 in Example 13, except that in this example, 2-piperidine is used instead of morpholine in Example 13, preparation steps are the same as in Example 13. Obtain 74mg of yellow solid (i.e. compound BIOS-B-21) (yield 58.60%). MS:445.2[M+H] + .

[0124] 1 H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.26(d,J=8.9Hz,2H),6.68(d,J=8.9Hz,2H),5.92(t,J=5.4Hz,1H),4.68~4.5 8(m,1H),4.32(s,1H),3.25~3.12(m,4H),2.86(s,1H),2.46~2.15(m,11H),2.14~2.03(m,2H),1.58~1.30(m,14H).

[0125] Example 22: Synthesis of 1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea (BIOS-B-22) [ka] The synthetic route for the compound is as follows. [ka] Refer to the synthesis method of compound BIOS-B-13 in Example 13, except that in this example, 4-methylpiperazine is used instead of morpholine in Example 13, the preparation steps are the same as in Example 13. Obtain 101mg of yellow solid (i.e. compound BIOS-B-22) (yield 85.58%). MS:416.2[M+H] + .

[0126] 1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.27(d,J=8.8Hz,2H),6.70(d,J=8.8Hz,2H),5.97(s,1H),4.68(s,1H) ),3.22~3.16(m,3H),3.05(s,2H),2.67(s,1H),2.44~2.04(m,14H),1.68~1.32(m,7H),1.29~1.08(m,3H).

[0127] Example 23: Synthesis of 1-(2-(3-hydroxypiperidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea (BIOS-B-23) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-13 in Example 13, except that in this example, 3-hydroxypiperidine is used instead of morpholine in Example 13, the preparation steps are the same as in Example 13. Obtain 103mg of yellow solid (i.e. compound BIOS-B-23) (yield 87.06%). MS:417.1[M+H] + .

[0128] 1 H NMR(400MHz,DMSO-d6)δ8.41(s,1H),7.26(d,J=9.2Hz,2H),6.68(d,J=9.2Hz,2 H),5.94(t,J=5.3Hz,1H),4.68~4.61(m,1H),4.61~4.53(m,1H),3.53~3.46(m, 1H),3.18~3.12(m,2H),2.91~2.78(m,2H),2.77~2.61(m,2H),2.43~2.17(m,8H ),2.14~2.03(m,2H),1.94~1.71(m,3H),1.67~1.57(m,1H),1.54~1.35(m,7H).

[0129] Example 24: Synthesis of 1-(2-(4-cyclobutylpiperazin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea (BIOS-B-24) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-13 in Example 13, except that in this example, 4-cyclobutylpiperazine hydrochloride is used instead of morpholine in Example 13, the preparation steps are the same as in Example 13. Obtain 70mg of white solid (i.e. compound BIOS-B-24) (yield 54.10%). MS:456.1[M+H] + .

[0130] 1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.25(d,J=9.0Hz,2H),6.67(d,J=9.0Hz,2H),5.92(s,1H),3.18~3.14(m,2H) ,2.88~2.80(m,1H),2.67(t,J=7.7Hz,1H),2.45~2.01(m,18H),1.93(s,2H),1.82~1.56(m,5H),1.55~1.32(m,6H).

[0131] Example 25: Synthesis of 2-morpholinyl-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide (BIOS-B-25) [ka] The synthetic route is as follows: [ka] Compound BIOS-B-1 (100 mg, 0.268 mmol) and Lawesson Reagent (108 mg, 0.268 mmol) were dissolved in 4 mL of anhydrous 1,4-dioxane and refluxed for 16 h. Thin layer chromatography showed that the raw materials were essentially completely reacted.

[0132] The reaction solution was concentrated to dryness and purified on a preparative plate (petroleum ether:ethyl acetate:triethylamine=5:4:1) to obtain 12 mg of a yellow solid (i.e., compound BIOS-B-25) (yield 11.46%). MS:390.1[M+H] + .

[0133] 1 H NMR(400MHz,DMSO-d6)δ9.59(s,1H),7.50(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),4.70~4.65(m,1H),3.7 0~3.54(m,4H),3.14(s,2H),2.88~2.81(m,1H),2.50~2.46(m,4H),2.37~2.00(m,8H),1.60~1.35(m,6H).

[0134] The synthesis route and preparation steps of compound BIOS-B-1 are omitted here for reference to Example 1.

[0135] Example 26: Synthesis of (R)-2-(2-methylpyrrolidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide (BIOS-B-26) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-25 in Example 25, except that in this example, BIOS-B-2 is used instead of BIOS-B-1 in Example 25, the preparation steps are the same as in Example 25. Obtain 38mg of yellow solid (i.e. compound BIOS-B-26) (yield 36.45%). MS:388.1[M+H] + .

[0136] 1 H NMR(400MHz,DMSO-d6)δ9.47(s,1H),7.50(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),4.69~4.64(m,1H),3.32(d,J=15.5Hz,1H),3.11~3.06(m,1H) ,2.90(d,J=15.5Hz,1H),2.88~2.81(m,1H),2.49~2.03(m,10H),1.97~1 .87(m,1H),1.81~1.60(m,2H),1.57~1.29(m,7H),1.06(d,J=6.1Hz,3H).

[0137] The synthesis route and preparation steps of compound BIOS-B-2 are omitted here, with reference to Example 2.

[0138] Example 27: Synthesis of 2-piperidinyl-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide (BIOS-B-27) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-25 in Example 25, except that in this example, BIOS-B-3 is used instead of BIOS-B-1 in Example 25, the preparation steps are the same as in Example 25. Obtain 29mg of yellow solid (i.e. compound BIOS-B-27) (yield 27.81%). MS:388.1[M+H] + .

[0139] 1 H NMR(400MHz,DMSO-d6)δ9.50(s,1H),7.50(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),4.70~4.65(m,1 H),3.10(s,2H),2.95~2.81(m,1H),2.44(t,J=5.3Hz,4H),2.38~2.03(m,8H),1.66~1.31(m,12H).

[0140] The synthesis route and preparation steps of compound BIOS-B-3 are omitted here, with reference to Example 3.

[0141] Example 28: Synthesis of 2-(N-methylhomopiperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide (BIOS-B-28) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-25 in Example 25, except that in this example, BIOS-B-4 is used instead of BIOS-B-1 in Example 25, the preparation steps are the same as in Example 25. Obtain 30mg of yellow solid (i.e. compound BIOS-B-28) (yield 37.90%). MS:417.1[M+H] + .

[0142] 1 H NMR(400MHz,DMSO-d6)δ9.53(s,1H),7.50(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),4.70~4.64(m,1H),3.28(s,2H),2.87~2.8 3(m,1H),2.80~2.71(m,4H),2.64~2.56(m,4H),2.38~2.14(m,9H),2.12~2.06(m,2H),1.83~1.71(m,2H),1.56~1.32(m,6H).

[0143] The synthesis route and preparation steps of compound BIOS-B-4 are omitted here, with reference to Example 4.

[0144] Example 29: Synthesis of 2-(diethylamino)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-29) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-1 in Example 1, except that in this example, diethylamine is used instead of morpholine in Example 1, the preparation steps are the same as in Example 1. Obtain 69mg of light yellow solid (i.e., compound BIOS-B-29) (yield 61.95%). MS:360.1[M+H] + .

[0145] 1 H NMR(400MHz,DMSO-d6)δ9.49(s,1H),7.50(d,J=8.8Hz,2H),6.75(d,J=8.8Hz,2H),4.70~4.65(m,1 H),3.18(s,2H),2.95~2.81(m,1H),2.44(t,J=5.5Hz,4H),2.29~2.08(m,8H),1.66~1.26(m,12H).

[0146] Example 30: Synthesis of 2-(dimethylamino)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-30) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-1 in Example 1, except that in this example, dimethylamine chloride is used instead of morpholine in Example 1, the preparation steps are the same as in Example 1. Obtain 51mg of light yellow solid (i.e., compound BIOS-B-30) (yield 49.67%). MS:332.1[M+H] + .

[0147] 1 H NMR(400MHz,DMSO-d6)δ9.56(s,1H),7.51(d,J=8.9Hz,2H),6.77(d,J=8.9Hz,2H),4.70~4.65(m,1 H),3.12(s,2H),2.95~2.82(m,1H),2.45(t,J=5.6Hz,4H),2.29~2.08(m,10H),1.66~1.26(m,6H).

[0148] Example 31: Synthesis of 2-(2-(dimethylamino)ethoxy)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide (BIOS-B-31) [ka] The synthetic route is as follows: [ka] Refer to the synthesis method of compound BIOS-B-1 in Example 1, except that in this example, N,N-dimethylethanolamine is used instead of morpholine in Example 1, the preparation steps are the same as in Example 1. Obtain 67mg of light yellow solid (i.e., compound BIOS-B-31) (yield 57.58%). MS:376.1[M+H] + .

[0149] 1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),7.53(d,J=8.6Hz,2H),6.85(d,J=8.6Hz,2H),4.65(t,J=9.9Hz,1H),4.16(s,2H),3.69(t,J= 6.7Hz,2H),3.02(t,J=6.3Hz,1H),2.81~2.69(m,5H),2.58~2.43(m,3H),2.36~2.30(m,3H),2.18~2.02(m,3H),1.57~1.38(m,8H).

[0150] Example 32: Histamine H3 receptor antagonist activity of compounds Using SUVN-G3031 as a positive control, 21 target compounds and one positive control compound were screened from the synthesized compounds by the 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.

[0151] Table 1: Histamine H3 receptor antagonist activity of compounds [Table 1]

[0152] 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.

[0153] Example 33: 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.

[0154] 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.

[0155] The results are shown in Table 2. Compounds BIOS-B-17 to BIOS-B-23, BIOS-B-8 to BIOS-B-15, BIOS-B-6, and BIOS-B-4 (10 μM) have an inhibition rate of less than 5% against the hERG channel. This shows that the test compounds basically have no hERG inhibitory activity, that is, the test compounds have good safety.

[0156] Table 2: Inhibition rate of compounds against hERG channel [Table 2] Here, "-" means not measured.

[0157] Example 34: Pain model activity data for compounds BIOS-B-12 and BIOS-B-14 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).

[0158] CCI model rats with stable mechanical sting thresholds were randomly divided into 5 groups, namely, model group, pregabalin (Pre) group (30mg / kg), BIOS-B-12 group (3mg / kg), BIOS-B-12 group (1mg / kg), and BIOS-B-12 group (0.3mg / kg), and administered orally at 1mL / 100g. The sham-operated group (sham) and model group (model) were administered orally with the same volume of saline. The basal value was measured before administration, and the mechanical sting pain threshold was detected 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after a single administration. The p value was calculated using one-way analysis of variance and T-test. The results are shown in Figure 1.

[0159] As a result, when compound BIOS-B-12 was administered to the SD rat CCI neuropathic pain model at three doses, 3 mg / kg, 1 mg / kg, and 0.3 mg / kg, the mechanical stinging pain threshold of the CCI model rats could be dose-dependently increased. The mechanical stinging pain threshold of 0.5 to 24 hours after administration of compound BIOS-B-12 (3 mg / kg) was significantly different from that of the model group (P<0.01), the mechanical stinging pain threshold of 0.5 to 6 hours after administration of compound BIOS-B-12 (1 mg / kg) was significantly different from that of the model group (P<0.01), the mechanical stinging pain threshold of 1 to 2 hours after administration of compound BIOS-B-12 (0.3 mg / kg) was significantly different from that of the model group (P<0.05), and when pregabalin was administered at 30 mg / kg, the mechanical stinging pain threshold of CCI rats increased only for 0.5 to 2 hours after administration, and was significantly different from the model group. This indicates that compound BIOS-B-12 has a longer duration of action and a superior analgesic strength to pregabalin.

[0160] CCI model rats with stable mechanical sting thresholds were randomly divided into four groups, namely, the model group, the pregabalin (Pre) group (30 mg / kg), and the BIOS-B-14 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 sting 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 analysis of variance and T-test. The results are shown in Figure 2.

[0161] As a result, when the compound BIOS-B-14 (1 mg / kg) was administered to the SD rat CCI neuropathic pain model, the mechanical pain threshold of the CCI model rats increased significantly, and the mechanical stinging pain threshold 0.5 to 4 hours after administration was significantly different from the threshold of the model group (P<0.05). When pregabalin was administered at 30 mg / kg, the mechanical stinging pain threshold of the CCI rats increased only at 0.5 and 1 hour after administration, and was significantly different from the model group. This indicates that the action time of the compound BIOS-B-14 is longer and superior to pregabalin.

[0162] Example 35: Activity data of compounds BIOS-B-12 and BIOS-B-18 in the pruritus model Male C57BL / 6J mice aged 6-8 weeks were randomly divided into a model group, a BIOS-B-12 compound group (10 mg / kg), a BIOS-B-18 compound group (10 mg / kg), and a dexamethasone (Dex) group (3 mg / kg) (7 mice / group). One hour after dexamethasone administration, four hours after BIOS-B-12 administration, and one hour after BIOS-B-18 administration, histamine was subcutaneously injected at 500 μg / 50 μl into the back of the neck of the mice. The mice were observed for 30 minutes, and the number of times the mice scratched was recorded. The inhibition rate was calculated as (model group-drug group) / model group×100%.

[0163] Table 3: Effect of BIOS-B-12 and BIOS-B-18 on the number of scratches in mice [Table 3]

[0164] As can be seen from Table 3, BIOS-B-12 (10 mg / kg) and BIOS-B-18 (10 mg / kg) can reduce the scratching frequency induced by histamine in mice. Furthermore, the effect of BIOS-B-18 was superior to that of the active drug dexamethasone.

Claims

1. A histamine H3 receptor inhibitor which is a compound having the following structural formula I or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (Wherein W is -(CH ２ ) ｍ -or-NR ６ (CH ２ ) ｍ - is selected from, X is selected from O or S; n ０ , n １ is selected from 1, 2, or 3; m is selected from 0, 1, 2, 3, 4, 5, or 6; R ０ is -NR'R'', -O(CH ２ ) ｍ NR'R'', a substituted or unsubstituted 5- to 8-membered heterocyclic group, and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituent on the heterocyclic group or heteroaryl group 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′ 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 groups selected from alkoxyamide groups, and R' and R'' cannot simultaneously be hydrogen; R １ , R ６ are each independently hydrogen, C １－６ alkyl group, —C(O)-alkyl group or —S(O) ２ - alkyl groups, R ２ , R ３ , R ４ , R ５ 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 ２ , R ３ together with the carbon atoms on the benzene ring to which they are respectively attached to form a substituted or unsubstituted benzobicyclic ring structure, said benzobicyclic ring structure including, but not limited to, benzoheterocycles; Or, R ４ , R ５ together with the carbon atoms on the benzene ring to which they are respectively attached to form a substituted or unsubstituted benzobicyclic ring structure, said benzobicyclic ring structure including, but not limited to, benzoheterocycles; R ７ , R ８ are each independently hydrogen, halogen, or C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, amino 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 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 alkoxy sulfoxide groups, Or, R ７ , R ８ form a ring with the nitrogen atom attached thereto, and the substituents on the ring are hydrogen, halogen, C １－６ Alkyl group, C １－６ Alkoxy 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 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 8-membered heterocyclic group, and a 3- to 8-membered heteroaryl group; The heterocyclic group, heteroaryl group, and benzoheterocycle contain at least one heteroatom, and the heteroatom is selected from N, O, and S.

2. 2. The histamine H3 receptor inhibitor of claim 1, which is a compound having the following structural formula II or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 wherein X is selected from O or S; n ０ , n １ is selected from 1, 2, or 3; m is selected from 0, 1, 2, 3, 4, 5, or 6; R ０ is -NR'R'', -O(CH ２ ) ｍ NR'R'', a substituted or unsubstituted 5- to 8-membered heterocyclic group, and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituent on the heterocyclic group or heteroaryl group 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′ 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 groups selected from alkoxyamide groups, and R' and R'' cannot simultaneously be hydrogen; R １ is hydrogen, C １－６ alkyl group, —C(O)-alkyl group or —S(O) ２ - alkyl groups, R ２ , R ３ , R ４ , R ５ 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 ２ , R ３ together with the carbon atoms on the benzene ring to which they are respectively attached to form a substituted or unsubstituted benzobicyclic ring structure, said benzobicyclic ring structure including, but not limited to, benzoheterocycles; Or, R ４ , R ５ together with the carbon atoms on the benzene ring to which they are respectively attached to form a substituted or unsubstituted benzobicyclic ring structure, said benzobicyclic ring structure including, but not limited to, benzoheterocycles; The heterocyclic group, heteroaryl group, and benzoheterocycle contain at least one heteroatom, and the heteroatom is selected from N, O, and S.

3. The histamine H3 receptor inhibitor according to claim 2, which is a compound having the following structural formula II-1 or a pharmaceutically acceptable salt thereof: 【Transformation 3】 wherein X is selected from O or S; m is selected from 1 or 2; R ０ is one selected from a substituted or unsubstituted 5- to 8-membered heterocyclic group and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituent on the heterocyclic group or heteroaryl group 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 １ is hydrogen, C １－６ alkyl group, —C(O)-alkyl group or —S(O) ２ - alkyl groups, R ２ , R ３ , R ４ , R ５ 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, The heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O, and S.

4. The histamine H3 receptor inhibitor according to claim 2, which is a compound having the following structural formula II-2 or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 wherein m is selected from 1 or 2; R ０ is -NR'R'', -O(CH ２ ) ｍ NR′R″, 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 groups selected from alkoxyamide groups, and R' and R'' cannot simultaneously be hydrogen; R １ is hydrogen, C １－６ alkyl group, —C(O)-alkyl group or —S(O) ２ - alkyl groups, R ２ , R ３ , R ４ , R ５ 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.)

5. 2. The histamine H3 receptor inhibitor of claim 1, which is a compound having the following structural formula III or a pharmaceutically acceptable salt thereof: 【Transformation 5】 wherein X is selected from O or S; n ０ , n １ is selected from 1, 2, or 3; m is selected from 0, 1, 2, 3, 4, 5, or 6; R ０ is one selected from a substituted or unsubstituted 5- to 8-membered heterocyclic group and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituent on the heterocyclic group or heteroaryl group 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 １ , R ６ are each independently hydrogen, C １－６ alkyl group, —C(O)-alkyl group or —S(O) ２ - alkyl groups, R ２ , 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 ２ , R ３ together with the carbon atoms on the benzene ring to which they are respectively attached to form a substituted or unsubstituted benzobicyclic ring structure, said benzobicyclic ring structure including, but not limited to, benzoheterocycles; Or, R ４ , R ５ together with the carbon atoms on the benzene ring to which they are respectively attached to form a substituted or unsubstituted benzobicyclic ring structure, said benzobicyclic ring structure including, but not limited to, benzoheterocycles; The heterocyclic group, heteroaryl group, and benzoheterocycle contain at least one heteroatom, and the heteroatom is selected from N, O, and S.

6. The histamine H3 receptor inhibitor according to claim 5, which is a compound having the following structural formula III-1 or a pharmaceutically acceptable salt thereof: 【Transformation 6】 (In the formula, n ０ , n １ is selected from 1, 2, or 3; m is selected from 0, 1, 2, 3, 4, 5, or 6; R ０ is one selected from a substituted or unsubstituted 5- to 8-membered heterocyclic group and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituent on the heterocyclic group or heteroaryl group 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, 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 an alkoxyamino group and a 3- to 6-membered cycloalkyl group; R ２ , 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 heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O, and S.

7. 2-morpholine-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, 2-(2-methylpyrrolidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, 2-(piperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, 2-(N-methylhomopiperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, 2-(4,4-difluoropiperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide 2-(4-hydroxypiperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, 2-(thiomorpholin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, 2-(2-(2-hydroxyethyl)piperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, 2-(piperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, 2-(4-methylpiperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, 2-(3-hydroxypiperidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, 2-(4-cyclobutylpiperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, 1-(2-morpholinoethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea, 1-(2-(2-methylpyrrolidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea, 1-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)-3-(2-(piperidin-1-yl)ethyl)urea, 1-(2-(piperazin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea, 1-(2-(N-methylhomopiperazin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea, 1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea, 1-(2-(4-hydroxypiperidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea, 1-(2-(thiomorpholin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea, 1-(2-(2-hydroxyethyl)piperidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea, 1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea, 1-(2-(3-hydroxypiperidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea, 1-(2-(4-cyclobutylpiperazin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea, 2-morpholinyl-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide, 2-(2-methylpyrrolidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide, 2-piperidinyl-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide, 2-(N-methylhomopiperazin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide, 2-(diethylamino)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, 2-(dimethylamino)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, or 2-(2-(dimethylamino)ethoxy)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide A histamine H3 receptor inhibitor which is a compound, isomer, solvate or pharmaceutically acceptable salt thereof having the structure:

8. (R)-2-(2-methylpyrrolidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)acetamide, (R)-1-(2-(2-methylpyrrolidin-1-yl)ethyl)-3-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)urea, or (R)-2-(2-methylpyrrolidin-1-yl)-N-(4-(3-(piperidin-1-yl)cyclobutoxy)phenyl)thioacetamide A histamine H3 receptor inhibitor which is a compound having the structure: or a pharmaceutically acceptable salt thereof.

9. 10. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

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

11. The use according to claim 10, wherein 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.

12. The use according to claim 10, wherein 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.

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