Derivatives of aryl aliphatic amines and uses thereof

Abstract

The present invention relates to derivatives of aryl fatty amines and their use for reducing local fat and weight. Specifically, disclosed are compounds of formula (I) or pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs thereof; and their use. The definition of each substituent group in the formula is described in the specification.

Description

Technical Field

[0001] This invention belongs to the field of medical technology and pharmaceuticals, specifically relating to derivatives of aryl fatty amines and their applications in medicine, namely, reducing localized fat and weight. Background Technology

[0002] In recent years, people's pursuit of beauty has become increasingly sophisticated, and their demands for body shape have become increasingly stringent. Especially for localized fat areas that are difficult to reduce through exercise and diet, such as the abdomen, thighs, buttocks, and upper arms, people seek various methods to achieve weight loss and slimming effects, but the results are often limited. According to Deloitte's "China Body Shaping Market Industry Development White Paper 2021," the current annual growth rate of China's medical aesthetics and body shaping industry has exceeded 20%, and the market is expected to reach a scale of hundreds of billions of yuan by 2030. A Medical Insight report shows that in 2020, the global market size for body shaping and skin tightening devices and disposable products was close to $1.3 billion. According to the 2023 China Body Shaping White Paper, in 2022, the penetration rate of China's body shaping market was only 1.2 per 1,000 people, far lower than in countries like the United States. The overall trend of fat reduction demand in China is shifting from traditional fat reduction and beauty treatments to more refined localized body shaping. The overall market potential is huge, and demand is growing year by year.

[0003] The well-known liposuction procedure was first applied clinically by Jeffrey Klein in 1987 [Jeffrey Klein, The Tumescent Technique for Lipo-Suction Surgery The American Journal of Cosmetic Surgery, 1987, 4(4): 263-267]. This method causes great damage to subcutaneous nerves and blood vessels, and has a large amount of bleeding and high surgical risk. In the past few decades, minimally invasive fat reduction techniques have been continuously developed. For example, ultrasonic lipolysis, cryolipolysis, and radiofrequency lipolysis have all become methods to reduce fat accumulation. However, there are still risks of side effects such as skin redness, pain, bruising, and infection. In addition, a certain recovery period is required after surgery, and the surgery is expensive. Minimally invasive fat reduction surgery is highly dependent on the doctor's skill level. The results are often not as obvious as traditional liposuction, and uneven skin texture caused by uneven fat removal still occurs. It does not meet the current clinical needs.

[0004] Jegasothy [Jegasothy S M. Deoxycholic acid injections for bra-line lipolysis[J]. Dermatol Surg,2018,44(5):757-760.] found that deoxycholic acid can effectively reduce excess fat in the armpits and upper back, while dieting, exercise, or minimally invasive procedures such as cryolipolysis often have little effect on fat reduction in these areas. Kybella is currently the only local lipolysis product that has been certified by the FDA and other multiple markets, and is used to eliminate local fat in areas such as the chin and cheeks. The main component is deoxycholic acid, and its mechanism of action is to dissolve and rupture the cell membrane of fat cells through deoxycholic acid, thereby expelling fat cell clusters from the body and achieving the effect of fat reduction [Jones DH, Carruthers J, Joseph JH, et al. REFINE-1, a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial with ATX-101, an injectable drug for submental fat reduction [J]. Dermatol Surg, 2016, 42(1):38-49.]. In order to achieve the fat-dissolving effect, dozens of injections are often required in one treatment, and injections are needed about once every two weeks. A total of 1-6 treatments are required, and the clinical compliance is not ideal.

[0005] In conclusion, there is an urgent need in this field to develop an effective method for reducing localized fat to meet the growing clinical demand. Summary of the Invention

[0006] The purpose of this invention is to provide a class of effective drugs for reducing localized fat and their uses.

[0007] A first aspect of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:

[0008]

[0009] A1 is selected from the following group: C3-C8 cycloalkyl, C6-C10 aryl, 5-10 heteroaryl;

[0010] A2 is selected from the following group: chemical bonds, saturated or partially unsaturated C3-C8 carbon rings, C3-C8 cycloalkyl groups, C6-C10 aryl groups, 5-10 heteroaryl groups, and C14-C24 saturated or unsaturated alkyl groups;

[0011] V is selected from the group consisting of: chemical bonds, substituted or unsubstituted C1-C6 alkylene groups, substituted or unsubstituted C3-C8 cycloalkyl groups, and substituted or unsubstituted 3-8 membered heterocyclic groups; the substitution refers to having one or more substituents selected from the group consisting of: deuterium, halogen, amino, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0012] W is selected from the group consisting of: chemical bonds, substituted or unsubstituted C1-C6 alkylene groups, substituted or unsubstituted saturated or partially unsaturated C3-C8 carbocyclic rings, substituted or unsubstituted 3-8 membered heterocyclic groups, and carbonyl groups; the substitution refers to having one or more substituents selected from the group consisting of: deuterium, halogen, amino, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0013] X is selected from the group consisting of N, P, and P=O; preferably, X is N.

[0014] L represents the linking group -(CH2). j -, the -(CH2) j One or more methylene groups in - are optionally selected from -NR 3’ -, -O-, -S-, -S(O)-, -S(O)NR 3’ -、-NR 3’ S(O)-, -S(O)2-, -S(O)2NR 3’ -、-NR 3’ S(O)2-、-NR 4’ S(O)2NR 3’ -、-CR 1’ R 2’ -, -C(O)-, -C(O)O-, -OC(O)-, -NR 3’ C(O)O-、-OC(O)NR 3’ -、-C(O)NR 3’ -、-NR 3’ C(O)-、-NR 4’ C(O)NR 3’ -, -P(O)-, -P(O)O-, -OP(O)-, -OP(O)O-, vinylene, ethynylene, C3-C12 cycloalkylene, or a group containing one or more 3-12-membered heteroalkylene groups selected from N, O, or S heteroatoms; wherein the methylene, vinylene, cycloalkylene, or heteroalkylene group is each optionally and independently substituted by one or more substituents selected from the group consisting of: halogen, -OR 3’ -NR 3’ R 4’ Oxylated, nitro, cyano, C1-C6 alkyl, -S(C1-C6 alkyl), C3-C10 cycloalkyl, 3-10 heterocyclic alkyl, -C(O)R 1’ -C(O)OR3’ -OC(O)R 1’ -C(O)NR 3’ -NR 3’ C(O)R 1’ -S(O)R 1’ -S(O)NR 3’ -S(O)2R 1’ -S(O)2NR 3’ -NR 3’ S(O)2R 1’ -NR 4’ S(O)2NR 3’ -OC(O)NR 3’ -NR 4’ C(O)NR 3’ ;R 1’ R 2’ Each can be independently a halogen, -OH, or -NR. 3’ R 4’ C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C10 cycloalkyl, -O(C3-C10 cycloalkyl), -NH(C3-C10 cycloalkyl), 3-10 membered heterocyclic alkyl, -O(3-10 membered heterocyclic alkyl), -NH(3-10 membered heterocyclic alkyl), R 3’ R 4’ Each is independently hydrogen, deuterium, C1-C6 alkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclic alkyl; j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0015] R1 is selected from the group consisting of: absent, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted benzene ring, substituted or unsubstituted 5-10 heteroaryl, wherein the substitution refers to having one or more substituents selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkylamino.

[0016] R2 is selected from the group consisting of: absent, halogen, cyano, trifluoromethanesulfonyl, nitro, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino (C1-C6 alkyl), substituted or unsubstituted N (C1-C6 alkyl)2, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic, substituted or unsubstituted C6-C10 aryl (preferably phenyl); the substitution refers to having one or more substituents selected from the group consisting of: deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl;

[0017] a and b can each independently be 0, 1, 2, 3, 4, 5 or 6;

[0018] Y is independently selected from the following group:

[0019] R4 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, and R4 together with the nitrogen attached thereto form substituted or unsubstituted 4- to 7-membered heterocyclic groups;

[0020] R5 is selected from the following group: hydrogen, substituted or unsubstituted C1-C6 alkyl groups, or...

[0021] Z - Anions that do not exist or are selected from the following group of acids: inorganic acids, organic acids, and amino acids;

[0022] --- indicates that there is no covalent bond;

[0023] When V and W are chemical bonds, and A2 is a partially unsaturated C3-C8 carbon ring, --- is a covalent bond, and the ring atoms in A1 and A2 that are connected to X, along with the ring atoms adjacent to them, together with X, form a 5-membered heteroaromatic ring.

[0024] Preferably, the inorganic acid is selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid;

[0025] Preferably, the organic acid is selected from: formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and deoxycholic acid.

[0026] Preferably, the amino acid is selected from: proline, phenylalanine, aspartic acid, and glutamic acid.

[0027] In another preferred embodiment, the compound is the compound represented by formula (II):

[0028]

[0029] R1, R2, A1, A2, V, W, L, Y, a, b are defined as above.

[0030] In another preferred embodiment, a and b are each independently 0, 1, 2, or 3.

[0031] In another preferred embodiment, A1 is selected from: substituted or unsubstituted C6-C10 aryl groups, substituted or unsubstituted 5-10 heteroaryl groups; preferably, A1 is selected from: substituted or unsubstituted phenyl groups, substituted or unsubstituted 5-6 heteroaryl groups; the substitution refers to having one or more substituents selected from the group consisting of: deuterium, halogen, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy.

[0032] In another preferred embodiment, A1 is selected from the following group:

[0033] In another preferred embodiment, A2 is selected from the group consisting of: saturated or partially unsaturated C3-C8 carbocyclic rings, C6-C10 aryl groups, 5-10 heteroaryl groups, and C14-C24 saturated or partially unsaturated alkyl groups.

[0034] In another preferred embodiment, A2 is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, thienyl, and thiazolyl, wherein the substitution refers to having one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

[0035] In another preferred embodiment, the compound is the compound represented by formula (III):

[0036]

[0037] Ring B is selected from the following group: substituted or unsubstituted C3-C8 carbocyclic groups, substituted or unsubstituted 3-8 membered heterocyclic groups;

[0038] R1, R2, L, and Y are defined as above.

[0039] In another preferred embodiment, the compound is the compound represented by formula (IV):

[0040]

[0041] R1, R2, V, W, L, Y, a, and b are defined as above.

[0042] In another preferred embodiment, a and b are each independently 0, 1, 2, or 3.

[0043] In another preferred embodiment, V is selected from the group consisting of: chemical bonds, C1-C3 alkylene groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, and carbonyl groups.

[0044] In another preferred embodiment, V is selected from the group consisting of: chemical bond, alkylene group, cyclopropyl group, cyclobutyl group, and carbonyl group.

[0045] In another preferred embodiment, W is selected from the group consisting of: chemical bonds, substituted or unsubstituted C1-C3 alkylene groups, substituted or unsubstituted C3-C6 cycloalkyl groups, substituted or unsubstituted 3-7 membered heterocyclic groups, and carbonyl groups; the substitution refers to having one or more substituents selected from the group consisting of: deuterium, halogen, amino, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0046] In another preferred embodiment, W is selected from the group consisting of: chemical bonds, It indicates a single or double bond.

[0047] In another preferred embodiment, R1 is selected from the group consisting of: F, Cl, Br, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyl, hydroxyl, amino, cyclohexyl, and cyano.

[0048] In another preferred embodiment, R2 is selected from the group consisting of: absent, F, Cl, Br, cyano, trifluoromethyl, and methoxy.

[0049] In another preferred embodiment, L is -(CH2). j -, the -(CH2) j One or more methylene groups in - are optionally replaced by a substituent selected from -C(O)-, -S(O)-, -O-, -S-, vinylene, ethynylene, cyclobutyl, or cyclopropyl; each of the methylene, vinylene, cyclobutyl, or cyclopropyl groups is independently and optionally replaced by one or more substituents selected from the group consisting of halogen, amino, or hydroxyl; j is 2, 3, 4, 5, 6, 7, or 8.

[0050] In another preferred embodiment, L is selected from: -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-; wherein one or more H in the methylene group are optionally substituted by one or more substituents selected from the group consisting of: halogen, amino, hydroxyl.

[0051] In another preferred embodiment, Y is selected from:

[0052] In another preferred embodiment, the compound is selected from the group consisting of:

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059] A second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and a pharmaceutically acceptable carrier.

[0060] A third aspect of the invention provides the use of the compounds described in the first aspect of the invention, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for reducing localized fat and body weight in a subject.

[0061] In another preferred embodiment, the localized fat includes areas selected from the group consisting of: face, chin, arms, waist, abdomen, and legs.

[0062] A fourth aspect of the present invention provides a method for reducing localized fat and weight in a subject, comprising:

[0063] The compound of formula (I) as described in the first aspect of the invention, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered to a subject in need.

[0064] In another preferred embodiment, the subjects include humans and non-human mammals (such as rats and monkeys).

[0065] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0066] Figure 1 This study demonstrates the changes in rat body weight after intraperitoneal injection of the compound of this application into rats fed a high-fat, high-glucose diet. Detailed Implementation

[0067] Through extensive and in-depth research, and through numerous screenings and tests, the inventors have for the first time discovered a class of small molecule compounds of formula (I). These compounds can effectively reduce localized fat and body weight, exhibiting superior efficacy compared to clinical candidates, while also demonstrating good safety. Based on this discovery, the present invention was completed.

[0068] the term

[0069] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0070] In this invention, "C1-C6 alkyl" refers to a straight-chain or branched alkyl group comprising 1 to 6 (1, 2, 3, 4, 5 or 6) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl or similar groups.

[0071] In this invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3-8 (1, 2, 3, 4, 5, 6, 7, or 8) carbon atoms on a ring, and non-limitingly includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The term "C..." 3-6 "Cycloalkyl" has a similar meaning.

[0072] In this invention, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1-6 carbon atoms, and non-limitingly includes methoxy, ethoxy, propoxy, isopropoxy, and butoxy, etc. Preferably, it is C1-C6 alkoxy. 1-4 Alkyl group.

[0073] In this invention, the term "haloalkyl" refers to a branched or straight-chain alkyl group substituted with one or more halogen atoms, up to the maximum permissible number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

[0074] In this invention, the term "heterocyclic group" refers to a 3-8 membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S. It may be used alone or in combination with other terms to refer to a saturated or partially saturated cyclic group consisting of 3-8 (3, 4, 5, 6, 7, or 8) ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur atoms may optionally be oxidized (i.e., C(=O), NO, SO, and SO2). It includes monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. Furthermore, heteroatoms may occupy the connection positions between the heterocyclic group and the rest of the molecule; heterocyclic groups include saturated and partially unsaturated heterocyclic groups. Non-limiting examples of heterocyclic groups include azirrobutyl, oxacyclobutyl, thioheterobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiophene (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuranyl-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, and homopiperidinyl.

[0075] In this invention, the terms "aromatic ring" or "aryl" have the same meaning, and are preferably "C". 6- C 10 "Aromatic". The term "C" 6- C 10"Aryl" refers to an aromatic cyclic group with 6-10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl and naphthyl.

[0076] In this invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to a heteroaromatic group containing one or more heteroatoms. For example, "5-10-membered heteroaryl" refers to an aromatic heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, and 2-7 carbon atoms. Non-limiting examples include: furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0077] A “carbocyclic” or “carbocyclic group” is a saturated or partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms. A carbocyclic group typically comprises one ring of 3 to 7 carbon atoms or two fused rings each containing 3, 4, 5, 6, or 7 carbon atoms. A cycloalkyl substituent may have a substituted nitrogen or carbon atom as a side chain, or the substituted carbon atom of two substituents may have a cycloalkyl group linked as a spiroyl group. Examples of carbocyclic groups include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl, and cyclopropyl rings. In one embodiment, the carbocyclic group is optionally substituted as described herein. In one embodiment, the cycloalkyl group is a partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms. In another embodiment, the cycloalkyl group is a saturated group containing all carbon ring atoms.

[0078] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. Such substituents include, but are not limited to: halogens, hydroxyl groups, carboxyl groups (-COOH), cyano groups (-CN), C1-C6 alkyl groups, C2-C6 alkenyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, etc.

[0079] In this invention, the terms 1-6 refer to 1, 2, 3, 4, 5, or 6. Other similar terms each have a similar meaning independently. The term "multiple" refers to 2-6 or more, such as 2, 3, 4, 5, or 6.

[0080] It should be understood that when a certain group exists simultaneously at multiple different positions in a compound, its definition at each position is independent of each other; they can be the same or different.

[0081] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures where enantiomers are enriched in diastereomers, all of which fall within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0082] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and deoxycholic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0083] Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0084] Compounds and their preparation methods

[0085] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

[0086]

[0087] The groups are defined as described above.

[0088] In another preferred embodiment, in the compound, any one of R1, R2, A1, A2, V, W, L, X, Y, a, b, --- is independently the corresponding group in the specific compound of the present invention.

[0089] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0090] Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0091] The methods for preparing compounds of formula (I) described below do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described herein or known in the art, such combinations being readily performed by those skilled in the art.

[0092] Pharmaceutical Compositions and Administration

[0093] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 5-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0094] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0095] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0096] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0097] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0098] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0099] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0100] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0101] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0102] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0103] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0104] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0105] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0106] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 5–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0107] The main advantages of this invention include:

[0108] (1) The compounds of the present invention have a significant inhibitory effect on the proliferation of differentiating adipocytes and mature adipocytes.

[0109] (2) The compounds of the present invention significantly inhibit the weight gain of rats fed a high-fat diet.

[0110] The following are abbreviations used in the instruction manual, reaction scheme, and examples:

[0111]

[0112] The following examples are provided to aid in understanding the invention, but should not be construed as limiting the invention as set forth in the following claims in any way.

[0113] A second aspect of the present invention provides a method for preparing the compound described in the first aspect, comprising the following steps:

[0114] Preparation method 1:

[0115]

[0116] (a) Compound I1 was reacted with 5-bromo-N,N,N-trimethylpentane-1-ammonium bromide under alkaline conditions to give compound I1.

[0117] I3;

[0118] Preparation method 2:

[0119]

[0120] (a) Equivalent amounts of dibromoalkyl compound II1 react with cyclic or acyclic tertiary amines or pyridine in a closed system under heating to yield bromoalkyl-substituted quaternary ammonium salt compound II2; where m = 5, 6, 7, and R1 is... Or cyclic quaternary ammonium salts,

[0121] (b) Compound II2 undergoes a substitution reaction with an aryl amine under alkaline conditions to give compound II3;

[0122] (c) Compound II3 undergoes a reductive amination reaction with an alkyl cyclic ketone to give compound II3; where n = 1, 2, 3, and R2 is a benzene ring or a substituted benzene ring.

[0123] Preparation method 3:

[0124]

[0125] (a) An indole derivative, III2, was synthesized by the Fischer indole synthesis method under heating conditions from equimolar amounts of phenylhydrazine III1 and an aryl-substituted cyclic ketone, where n = 1, 2.

[0126] (b) Compound II2 reacts with a trimethyl or triethyl quaternary ammonium alkyl bromide under alkaline conditions to give compound III3; wherein m = 5

[0127] Example 1

[0128] Compound 1: 5-(di(4-bromophenyl)amino)-N,N,N-trimethylpentane-1-ammonium bromide

[0129]

[0130] Synthesis route:

[0131]

[0132] Step a: Weigh out bis(4-bromophenyl)amine (4.00 g, 12.3 mmol), 5-bromo-N,N,N-trimethylpentane-1-ammonium bromide (3.91 g, 13.5 mmol), cesium carbonate (12.00 g, 36.9 mmol), and sodium iodide (184 mg, 1.2 mmol) sequentially into a round-bottom flask. Measure out N,N-dimethylformamide (80 mL) and add it to the reaction flask. Heat the reaction solution to 60 °C and react for 5 h. Cool down, filter the reaction solution, pour the filtrate into 200 mL of water, add ethyl acetate (300 mL) for extraction, extract the aqueous phase with dichloromethane (400 mL), concentrate under reduced pressure to obtain a concentrated solution, dilute the concentrated solution with 200 mL of water, extract the aqueous phase with n-butanol (300 mL), combine the organic phases, wash the organic phase again with 100 mL of water, concentrate the organic phase under reduced pressure to obtain a crude viscous oily substance. The crude product was dissolved in DCM (10 mL), and ether was added dropwise until a white powder precipitated. The mixture was filtered, and the filter cake was dried under vacuum to obtain a white powder (2.065 g, 32%).

[0133] 1 H NMR: (300MHz, DMSO-d6)δ7.44(d,J=8.9Hz,4H),6.95(d,J=8.9Hz,4H),3.68(t,J= 7.5Hz,2H),3.31-3.20(m,2H),3.03(s,9H),1.74-1.51(m,4H),1.36-1.23(m,2H).

[0134] LCMS m / z 455.05 [M] + .

[0135] Example 2

[0136] Compound 2: 5-((4-bromophenyl)(cyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0137]

[0138] Synthesis route:

[0139]

[0140] Step a: Weigh 4-bromoaniline (1.71 g, 10.0 mmol), 5-bromo-N,N,N-trimethylpentane-1-ammonium bromide (1.45 g, 5.0 mmol), and cesium carbonate (9.75 g, 30.0 mmol) sequentially into a round-bottom flask. Add NMP (12 mL) to the reaction flask and stir overnight at room temperature. Dilute the reaction solution with water (50 mL), extract with EA (60 mL), extract the aqueous phase with n-butanol, and concentrate under reduced pressure to obtain 5-((4-bromophenyl)amino)-N,N,N-trimethylpentyl-1-ammonium bromide (1.10 g), which can be used directly in the next synthesis without purification.

[0141] Step b: Weigh 5-((4-bromophenyl)amino)-N,N,N-trimethylpentyl-1-ammonium bromide (500 mg, 1.32 mmol), cyclohexyl ketone 2-4 (190 mg, 1.94 mmol), SiEt3H (582 mg, 5.06 mmol), and SnCl2 (150 mg, 0.8 mmol) into a round-bottom flask. Add 8 mL of methanol to the reaction flask and heat to 70 °C for 4 h. Cool the reaction solution, concentrate under reduced pressure, and purify by silica gel column chromatography. Elute with DCM-MeOH (10:1-5:1) to obtain compound 2 (10 mg, 1.6%).

[0142] 1 H NMR (300MHz, CD3OD) δ7.29 (d, J = 8.1Hz, 2H), 6.78 (s, 2H), 3.52 (s, 1H), 3.40-3.34 (m, 2H), 3. 27(d,J=12.0Hz,2H),3.15(s,9H),1.91-1.73(m,6H),1.72-1.50(m,4H),1.50-1.33(m,6H).

[0143] LCMS m / z 381.15 [M] + .

[0144] Example 3

[0145] Compound 3: 5-((4-bromophenyl)(4-phenylcyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0146]

[0147] Synthesis route:

[0148]

[0149] Step a: Weigh 1,5-dibromopentane (1.00 g, 4.35 mmol) and trimethylamine (0.25 g, 4.35 mmol) and dissolve them in 10 mL of LEtOH. The system was sealed and heated to 80 °C with stirring for 24 h. The reaction solution was concentrated under reduced pressure to obtain 500 mg of crude 5-bromo-N,N,N-trimethylpentane-1-ammonium bromide, which was directly used in the next synthesis step.

[0150] Step b: Weigh 4-bromoaniline (0.41 g, 2.4 mmol), 5-bromo-N,N,N-trimethylpentane-1-ammonium bromide (0.5 g, 2.0 mmol), and cesium carbonate (998 mg, 4.0 mmol) sequentially into a round-bottom flask. Add 10 mL of MeOH to the reaction flask and heat to 75 °C with stirring overnight. After concentrating the reaction solution, purify it by silica gel column chromatography using DCM-MeOH (10:1) to obtain 5-((4-bromophenyl)amino)-N,N,N-trimethylpentane-1-ammonium bromide (200 mg, 29%). This was used directly in the next synthesis.

[0151] Step c: Weigh 5-((4-bromophenyl)amino)-N,N,N-trimethylpentane-1-ammonium bromide (200 mg, 0.58 mmol), 4-phenylcyclohexanone (122 mg, 0.7 mmol), Et3SiH (200 mg, 1.7 mmol), and stannous chloride dihydrate (180 mg, 0.8 mmol) into a hard glass tube. Add 3 mL of methanol to the tube and heat to 70 °C for 12 h. Cool the reaction solution, quench with water, extract with EA, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography. Elute with DCM-MeOH (20:1) to give compound 3, 20 mg, yield 17%.

[0152] 1 H NMR(300MHz,DMSO-d6)δ7.39-7.14(m,7H),6.73(t,J=9.8Hz,2H),3.68(s,br,1 H), 3.18 (s, 4H), 3.03 (d, J = 14.9Hz, 9H), 1.90-1.48 (m, 11H), 1.34-1.16 (m, 4H).

[0153] LCMS m / z 457.20 [M] + .

[0154] Example 4

[0155] Compound 4: 5-((4-bromophenyl)(cis-4-phenylcyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium iodide

[0156]

[0157] Synthesis route:

[0158]

[0159] Step a: Weigh p-bromoaniline (2.94 g, 17.1 mmol), 5-bromopentanol (2.60 g, 15.5 mmol), and K2CO3 (4.3 g, 31.1 mmol) into a round-bottom flask. Add 50 mL of ACN to the reaction flask and heat to 80 °C for 16 h. Cool the reaction solution, quench with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography. Elute with PE-EA (1:0-3:1) to obtain 5-((4-bromophenyl)amino)pentanol 4-3 (1.27 g, 32%).

[0160] 1 H NMR (300MHz, CDCl3) δ7.26-7.20(m,2H),6.50-6.43(m,2H),3.75(t,J=6.7Hz,1H),3.67(t,J=6.3 Hz, 2H), 3.09 (t, J = 7.0 Hz, 2H), 1.63 (dd, J = 14.7, 7.5 Hz, 4H), 1.48 (ddd, J = 13.1, 6.0, 2.9 Hz, 2H).

[0161] Step b: Weigh 5-((4-bromophenyl)amino)pentanol (1.25 g, 4.8 mmol), 4-phenylcyclohexanone (5.06 g, 29.0 mmol), and SnCl2 (1.64 g, 7.26 mmol) into a round-bottom flask. Dissolve the substrate in 30 mL of methanol. Add Et3SiH (1.68 g, 14.5 mmol) dropwise to the reaction solution. After the addition is complete, heat to 70 °C and react for 16 h. Cool the reaction solution, quench with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography. Elute with PE-EA (1:0-5:1) to obtain 5-((4-bromophenyl)(4-phenylcyclohexyl)amino)pentanol (1.80 g, 89%).

[0162] LCMS m / z 416.15 [M+H] + .

[0163] Step c: Weigh imidazole (687 mg, 10.1 mmol) and PPh3 (2.65 g, 10.1 mmol) into a round-bottom flask. Measure 20 mL of DCM and add it to the reaction flask. Weigh I2 (2.56 g, 10.1 mmol) and add it to the reaction solution. Stir at room temperature for 30 min. Weigh 5-((4-bromophenyl)(4-phenylcyclohexyl)amino)pentanol (1.80 g, 4.3 mmol), dissolve it in 20 mL of THF, and then add it dropwise to the reaction solution. React at 20 °C for 16 h. Filter the reaction solution, quench the filtrate with saturated sodium sulfite solution, extract with DCM, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography. Elute with PE-EA (1:0-50:1) to obtain:

[0164] 5-((4-bromophenyl)(cis-4-phenylcyclohexyl)amino)iodopentane cis-4-6 (160 mg, 7%), LCMS m / z 526.05 [M+H] + ;

[0165] 5-((4-bromophenyl)(trans-4-phenylcyclohexyl)amino)iodopentane trans-4-6 (480 mg, 21%), LCMS m / z 526.05 [M+H] + .

[0166] Step d: Weigh 120 mg (0.2 mmol) of 5-((4-bromophenyl)(cis-4-phenylcyclohexyl)amino)iodopentane and dissolve it in 2 mL of trimethylamine ethanol solution. Heat the solution to 65 °C and react for 3 h. After the reaction solution is concentrated under reduced pressure, it is separated by silica gel column chromatography and eluted with DCM-MeOH (100:1-10:1) to obtain 26 mg (19%) of 5-((4-bromophenyl)(cis-4-phenylcyclohexyl)amino)-N,N,N-trimethylpentane-1-iodide.

[0167] 1 H NMR (300MHz, CD3OD) δ7.38-7.13(m,7H),6.82-6.76(m,2H),3.63(td,J=8.2,4.0Hz,1H),3.35-3.31(m,1H),3.26(d,J=4.5Hz,1H),3.08( d,J=4.7Hz,9H),3.04(s,1H),2.95-2.90(m,1H),2.31-2.16(m,2H),1.94-1.59(m,9H),1.54-1.44(m,2H),1.30(dd,J=14.0,6.6Hz,2H).

[0168] LCMS m / z 457.20 [M] +.

[0169] Example 5

[0170] Compound 5: 5-((4-bromophenyl)(trans-4-phenylcyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium iodide

[0171]

[0172] Synthesis route:

[0173]

[0174] Step a: Weigh 480 mg (0.9 mmol) of 5-((4-bromophenyl)(trans-4-phenylcyclohexyl)amino)iodopentane trans-4-6 obtained in step c of Example 4, dissolve it in 5 mL of trimethylamine ethanol solution, and react at 65 °C for 3 h; after the reaction solution is concentrated under reduced pressure, it is separated by silica gel column chromatography and eluted with DCM-MeOH (100:1-10:1) to obtain 45 mg (8%) of 5-((4-bromophenyl)(trans-4-phenylcyclohexyl)amino)-N,N,N-trimethylpentane-1-iodide.

[0175] 1 H NMR (300MHz, CD3OD) δ7.29-7.22(m,6H),7.18-7.13(m,1H),6.74(d,J=9.1Hz,2H),3.66(s,1H),3.45-3.36(m,2H),3.29-3.21(m,2H) ,3.16(s,9H),2.56(s,1H),2.48-2.30(m,1H),1.93-1.89(m,3H),1.84(dd,J=10.1,6.4Hz,2H),1.72-1.61(m,6H),1.47-1.39(m,2H).

[0176] LCMS m / z 457.15 [M] + .

[0177] Example 6

[0178] Compound 6: 5-(diphenylphosphine)-N,N,N-trimethylpentane-1-ammonium bromide

[0179]

[0180] Synthetic route

[0181]

[0182] Step a: Weigh 500 mg (2.5 mmol) of diphenylphosphine oxide and dissolve it in 5 mL of DMF. Cool the temperature to 0 °C. Weigh 119 mg (5.0 mmol) of sodium hydroxide and add it to the reaction solution. Stir at 0 °C for 10 min. Then weigh 621 mg (3.0 mmol) of 5-bromo-N,N,N-trimethylpentane-1-ammonium bromide and add it to the reaction solution. React at room temperature overnight. Quench the reaction solution with water and extract with EA. Wash the organic phase with saturated brine. After concentration under reduced pressure, separate and purify the compound 6 (34 mg, 4%) by preparative HPLC (C18 silica gel bonded phase).

[0183] 1 H NMR(300MHz,CD3OD)δ7.55(s,1H),7.05-6.91(m,4H),6.80-6.71(m,5H),2.50(s,2H),2.29(s, 9H), 1.67 (dd, J = 15.9, 10.9 Hz, 2H), 0.98 (s, 2H), 0.86 (d, J = 7.6 Hz, 2H), 0.71 (d, J = 6.9 Hz, 2H).

[0184] LCMS m / z 330.15 [M] + .

[0185] Example 7

[0186] Compound 7: 5-(di-(4-bromophenyl)phosphine)-N,N,N-trimethylpentane-1-ammonium bromide

[0187]

[0188] Compound 7 was obtained by replacing 6-1 in Example 6 with compound 7-1, and synthesizing it according to the same method as compound 6.

[0189] 1 H NMR(300MHz,CD3OD)δ7.66(m,4H),7.74(s,4H),2.49(s,2H),2.28(s,9H),1.66(d d,J=15.9,10.9Hz,2H),0.99(s,2H),0.88(d,J=7.6Hz,2H),0.70(d,J=6.9Hz,2H).

[0190] LCMS m / z 488.01 [M] + .

[0191] Example 8

[0192] Compound 8: N 1 -(4-Bromophenyl)-N 5 N5 -dimethyl-N 1 -(4-phenylcyclohexyl)pentane-1,5-diamine

[0193]

[0194] Synthesis route:

[0195]

[0196] Step a: Weigh imidazole (687 mg, 10.1 mmol) and triphenylphosphine (2.65 g, 10.1 mmol) and dissolve them in 20 mL of DCM. Weigh elemental iodine (2.56 g, 10.1 mmol) and add it to the reaction solution. Stir the reaction solution at room temperature for 20 minutes. Weigh 5-((4-bromophenyl)(4-phenylcyclohexyl)amino)-1-pentanol (1.80 g, 4.3 mmol) and dissolve it in 20 mL of DCM. Add it dropwise to the reaction solution and react at room temperature for 16 h. Filter the reaction solution, quench the filtrate with sodium sulfite solution, extract with DCM, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography. Elute with PE-EA (50:1) to obtain 4-bromo-N-(5-iodopentyl)-N-(4-phenylcyclohexyl)amine (640 mg, 28%).

[0197] Step b: Weigh 100 mg (0.2 mmol) of N-(4-bromophenyl)-N-(5-iodopentyl)-N-(4-phenylcyclohexyl)amine and dissolve it in 2 mL of Me2NH / THF solution. React at room temperature for 16 h. After the reaction solution is concentrated, it is purified by preparative HPLC and eluted with DCM-MeOH (10:1) to obtain compound 8 (5 mg, 6%).

[0198] 1 H NMR (300MHz, CD3OD) δ7.44-7.22 (m, 6H), 7.16 (dt, J=11.3, 8.0Hz, 1H), 6.74 (dd, J=21.5, 9.1Hz, 2H),3.63(d,J=5.1Hz,1H),3.25-3.19(m,1H),3.08-3.01(m,1H),2.91-2.72(m,2H),2.63(d,J= 15.2Hz,6H),2.21(s,1H),1.89(dd,J=16.1,6.8Hz,2H),1.83-1.69(m,2H),1.65(d,J=9.2Hz,2H ),1.61-1.53(m,2H),1.48-1.37(m,2H),1.31(d,J=6.3Hz,1H),1.23(s,1H),0.99-0.78(m,2H).

[0199] LCMS m / z 443.20 [M+H] + .

[0200] Example 9

[0201] Compound 9: N 1 -(4-Bromophenyl)-N 1 -(4-phenylcyclohexyl)pentane-1,5-diamine

[0202]

[0203] Synthesis route:

[0204]

[0205] Step a: Weigh N-(4-bromophenyl)-N-(5-iodopentyl)-N-(4-phenylcyclohexyl)amine (200 mg, 0.4 mmol) and potassium phthalimide (55 mg, 0.4 mmol) into a round-bottom flask. Add 2 mL of DMF to the reaction flask and heat to 45 °C for 4 h. Quench the reaction solution with water, extract with EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and separate by silica gel column chromatography using PE-EA (1:0-3:1) to obtain 2-(5-((4-bromophenyl)(4-phenylcyclohexyl)amino)pentyl)isoindoline-1,3-dione (150 mg, 72%). LCMS m / z 545.2 [M+H] + .

[0206] Step b: Weigh 150 mg (0.27 mmol) of 2-(5-((4-bromophenyl)(4-phenylcyclohexyl)amino)pentyl)isoindoline-1,3-dione into a round-bottom flask, add 30 mL of ethanol to the reaction flask, and add 133 mg (0.27 mmol) of hydrazine hydrate dropwise to the reaction solution. Heat the mixture to 80 °C and react for 2 h. Cool the reaction solution, concentrate it under reduced pressure, and then purify it by silica gel column chromatography. Elute with DCM-MeOH (10:1) to obtain compound 9 (66 mg, 57%).

[0207] 1H NMR (300MHz, CD3OD) δ7.36-7.06(m,7H),6.79-6.65(m,2H),3.69-3.56(m,1H),3.253.01(m,2H),2.98-2.81(m,2H),2.49(dd,J=14.7,8 .4Hz,1H),2.22(d,J=14.4Hz,1H),1.87(t,J=11.8Hz,2H),1.78-1.47(m,8H),1.43(dd,J=9.5,6.0Hz,2H),1.30(dd,J=13.8,6.6Hz,1H).

[0208] LCMS m / z 415.10 [M+H] + .

[0209] Example 10

[0210] Compound 10: 5-((4-bromophenyl)(4-phenylcyclohexyl)amino)pentamidine

[0211]

[0212] Synthesis route:

[0213]

[0214] Step a: Weigh 4-bromoaniline (2.00 g, 11.6 mmol), 5-bromopentonitrile (1.88 g, 11.6 mmol), and cesium carbonate (7.56 g, 23.2 mmol) and mix them in 20 mL of acetonitrile. Heat the mixture to 70 °C and react for 12 h. Quench the reaction solution with 20 mL of water, extract with EA, wash the organic phase with saturated brine, concentrate under reduced pressure, and then purify by silica gel column chromatography. Elute with PE-EA (4:1) to obtain 5-((4-bromophenyl)amino)-1-pentonitrile (500 mg, 17%). 1 H NMR (300MHz, CDCl3) δ7.26 (d, J = 1.1 Hz, 1H), 7.24-7.21 (m, 1H), 6.50-6.44 (m, 2H), 3.14 (dd, J = 7.6, 5.4Hz, 2H), 2.44-2.36 (m, 2H), 1.83-1.72 (m, 4H).

[0215] Step b: Weigh 5-((4-bromophenyl)amino)-1-pentanilonitrile (500 mg, 2.0 mmol), 4-phenylcyclohexanone (410 mg, 2.4 mmol), stannous chloride dihydrate (800 mg, 3.0 mmol) and Et3SiH (828 mg, 7.0 mmol) and mix them in 10 mL of methanol. Heat the mixture to 75 °C and react for 12 h. Cool the reaction mixture and quench it with 20 mL of water. Extract the mixture with EA. Wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate, concentrate it under reduced pressure, and then purify it by silica gel column chromatography. Elute the mixture with PE-EA (5:1) to obtain 5-((4-bromophenyl)(4-phenylcyclohexyl)amino)-1-pentanilonitrile (150 mg, 18%).

[0216] Step c: Weigh 80 mg (0.2 mmol) of 5-((4-bromophenyl)(4-phenylcyclohexyl)amino)-1-pentanilonitrile and dissolve it in 0.3 mL of 1,4-dioxane and 75 μL of methanol. Cool to -10 °C and stir for 1 h. Add 0.3 mL of 4 M HCl dioxane solution dropwise. After the addition is complete, raise the temperature to room temperature and react for 4 h. Concentrate the reaction solution under reduced pressure to obtain crude 1-methoxy-5-((4-bromophenyl)(4-phenylcyclohexyl)amino)-pentyl-1-imine (50 mg), which is used directly in the next synthesis without purification.

[0217] Step d: Weigh 330 mg (0.74 mmol) of crude 1-methoxy-5-((4-bromophenyl)(4-phenylcyclohexyl)amino)-pentyl-1-imine and dissolve it in 1 mL of ammonia-methanol solution. React at room temperature for 1 h. After concentration under reduced pressure, the product is purified by silica gel column chromatography and eluted with PE-EA (5:1) to obtain compound 10 (150 mg, 47%).

[0218] 1 H NMR (300MHz, CD3OD) δ7.30-7.20(m,6H),7.18-7.10(m,1H),6.74(d,J=9.1Hz,2H),3.66(s ,1H),3.26(d,J=7.8Hz,1H),2.58-2.44(m,3H),1.92(d,J=6.9Hz,4H),1.82-1.56(m,9H).

[0219] LCMS m / z 428.10 [M+H] + .

[0220] Example 11

[0221] Compound 11: 5-((4-bromophenyl)(4-phenylcyclohexyl)amino)-N,N,N-triethylpentyl-1-ammonium chloride

[0222]

[0223] By replacing 3-2 in Example 3 with compound 11-1, and following the same synthesis method as compound 3, compound 11 was obtained, 55 mg, in 18% yield.

[0224] 1 H NMR(300MHz,CD3OD)δ7.37-7.09(m,7H),6.76(dd,J=22.2,8.5Hz,2H),3.63(s,1H),3.38-3.19(m,9H),3.08 -2.94(m,2H),2.51(br,1H),2.21(br,1H),1.92(br,3H),1.75-1.59(m,7H),1.46(s,2H),1.34-1.17(m,9H).

[0225] LCMS m / z 499.25 [M] + .

[0226] Example 12

[0227] Compound 12: N,N,N-Trimethyl-5-(phenyl(4-phenylcyclohexyl)amino)pentyl-1-ammonium chloride

[0228]

[0229] By replacing compounds 3-4 in Example 3 with compound 12-1, and following the same synthetic method as compound 3, compound 12, 62 mg, was obtained in 23% yield.

[0230] 1 H NMR (300MHz, CD3OD) δ7.38-7.31(m,4H),7.26-7.08(m,6H),3.75(s,1H),3.53(s,1H),3.36(s,1H),3.25(s ,1H),3.10(d,J=10.8Hz,9H),2.89(s,1H),2.52(s,1H),1.98(s,2H),1.88-1.53(m,9H),1.51-1.30(m,3H).

[0231] LCMS m / z 379.25 [M] + .

[0232] Example 13

[0233] Compound 13: (R)-4-((4-bromophenyl)(4-phenylcyclohexyl)amino)-2-hydroxy-N,N,N-trimethyl-4-carbonylbutane-1-ammonium chloride

[0234]

[0235] Synthesis route:

[0236]

[0237] Step a: Weigh 4-bromoaniline (500 mg, 2.9 mmol) and 4-phenylcyclohexanone (513 mg, 2.9 mmol) and dissolve them in 10 mL MeOH. Add acetic acid to adjust the pH of the system to 5-6. Weigh NaBH3CN (252 mg, 4.0 mmol) and add it to the reaction system. React at room temperature for 30 min. Concentrate the reaction solution under reduced pressure, dilute with 10 mL of water, extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography. Elute with PE-EA (5:1) to obtain 4-bromo-N-(4-phenylcyclohexyl)amine (577 mg, 60%).

[0238] Step b: Weigh L-carnitine (200 mg, 1.2 mmol), 4-bromo-N-(4-phenylcyclohexyl)amine (395 mg, 1.2 mmol), DIEA (0.5 mL, 3.7 mmol), and PyBOP (970 mg, 2.5 mmol) into a round-bottom flask. Measure 10 mL of DCM and add it to the reaction flask. React at room temperature for 12 h. Add water to the reaction solution and adjust the pH to 3-4 with 1N hydrochloric acid. Extract with EA, combine the organic phases, wash with saturated brine, concentrate under reduced pressure, and purify by silica gel column chromatography. Elute with DCM-MeOH (100:1-50:1) to obtain compound 13 (150 mg, 18%).

[0239] 1 H NMR (300MHz, DMSO-d6) δ7.40-7.15(m,7H),6.75(t,J=9.8Hz,2H),4.58-4.41(m,1H ),3.41-3.25(m,3H),3.10(d,J=14.9Hz,9H),2.73-2.58(m,3H),1.85-1.55(m,8H).

[0240] LCMS m / z 473.17 [M] + .

[0241] Example 14

[0242] Compound 14: 2-((5-((4-bromophenyl)(4-phenylcyclohexyl)amino)pentyl)dimethylammonium)acetate

[0243]

[0244] Synthesis route:

[0245]

[0246] Step a: Weigh compound 8 (100 mg, 0.22 mmol) and methyl chloroacetate (36 mg, 0.35 mmol) into a round-bottom flask, add DMF to the reaction flask, and react at 60 °C for 18 h; add water to the reaction solution, extract with DCM, wash with saturated brine, concentrate under reduced pressure, and purify by silica gel column chromatography, eluting with DCM-MeOH (100:1-80:1) to obtain 5-((4-bromophenyl)(4-phenylcyclohexyl)amino)-N-(methoxyacylethyl)-N,N-dimethylpentylammonium chloride (39 mg, 30%).

[0247] LCMS m / z 516.22 [M+H] + .

[0248] Step b: Weigh compound 8 (35 mg, 0.06 mmol) and lithium hydroxide (10 mg, 0.41 mmol) into a round-bottom flask. Measure 0.5 mL of THF and 0.5 mL of water and add them to the reaction flask. Stir at room temperature for 9 h. Concentrate the reaction solution under reduced pressure, adjust the pH to 3-4 with 1 N hydrochloric acid, extract with EA, wash with saturated brine, concentrate under reduced pressure, and purify by silica gel column chromatography. Elute with DCM-MeOH (50:1-20:1) to obtain compound 17 (20 mg, 63%).

[0249] 1 H NMR (300MHz, CD3OD) δ7.80 (dd, J=13.8, 8.8Hz, 2H), 7.63 (dd, J=17.1, 8.8Hz, 2 H),7.38(d,J=7.6Hz,1H),7.33-7.22(m,2H),7.21-7.11(m,2H),4.26(d,J=7.0 Hz,2H),3.93-3.66(m,3H),3.53(dd,J=17.1,10.4Hz,2H),3.25(d,J=7.3Hz,6H ),3.16-2.84(m,1H),2.61-2.26(m,2H),2.09-1.54(m,9H),1.49-1.29(m,3H).

[0250] LCMS m / z 501.21 [M+H] + .

[0251] Example 15

[0252] Compound 15: (R)-4-((4-bromophenyl)(4-phenylcyclohexyl)amino)-2-hydroxy-N,N,N-trimethylbutane-1-ammonium chloride

[0253]

[0254] Synthesis route:

[0255]

[0256] Step a: Weigh 13 (100 mg, 0.21 mmol) and dissolve it in 1 mL of THF. Add the solution dropwise to a 1 mL THF solution of lithium aluminum hydride (16 mg, 0.42 mmol) at 0 °C. After the addition is complete, raise the temperature to room temperature and react for 4 h. Cool the temperature to 0 °C, quench the reaction solution with water, add 15% sodium hydroxide solution, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography. Elute with DCM-MeOH (50:1-20:1) to obtain compound 15 (24 mg, 21%).

[0257] 1 H NMR(300MHz,DMSO-d6)δ7.39-7.13(m,7H),6.73(t,J=9.6Hz,2H),4.58-4.41(m,1H),3.41-3 .15(m,5H),3.10(d,J=15.2Hz,9H),2.73-2.68(m,1H),1.85-1.55(m,8H),1.50-1.42(m,2H);

[0258] LCMS m / z 459.20 [M] + .

[0259] Example 16

[0260] Compound 16: 5-((4-bromophenyl)(cycloheptyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0261]

[0262] By replacing compounds 2-4 in Example 2 with compound 16-1, and following the same synthesis method as compound 2, compound 16 was obtained, 13 mg, in 12% yield.

[0263] 1H NMR (400MHz, CD3OD) δ7.24(d,J=8.8Hz,2H),6.66(d,J=8.8Hz,2H),3.72-3.63(m,1H),3.20-3.15(m,2H),3 .14-3.09(m,2H),3.11(s,9H),1.88-1.73(m,6H),1.72-1.58(m,8H),1.55-1.50(m,2H),1.44-1.36(m,2H).

[0264] LCMS m / z 395.20 [M] + .

[0265] Example 17

[0266] Compound 17: 5-((4-bromophenyl)(cyclopentyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0267]

[0268] By replacing compounds 2-4 in Example 2 with compound 17-1, and following the same synthesis method as compound 2, compound 17, 31 mg, was obtained in 42% yield.

[0269] 1 H NMR (300MHz, CD3OD) δ7.80(d,J=8.3Hz,2H),7.70(d,J=8.8Hz,2H),4.19(s,1H),3.68(s,2H),3.12(d,J=12.6Hz,9H),2.44-1.12(m,16H).

[0270] LCMS m / z 367.10 [M] + .

[0271] Example 18

[0272] Compound 18: 4-((4-bromophenyl)(4-phenylcyclohexyl)amino)-N,N,N-trimethylbutane-1-ammonium chloride

[0273]

[0274] By replacing 3-3 in Example 3 with compound 18-1, and following the same synthetic method as compound 3, compound 18 was obtained, 50 mg, in a yield of 24%.

[0275] 1H NMR(400MHz,CD3OD)δ7.83-7.70(m,4H),7.27-7.15(m,5H),3.86-3.79(m,2H),3.69-3.58(m,2H), 3.11(d,6.0Hz,9H),2.95-2.88(m,1H),2.56-2.49(m,1H),2.02-1.59(m,10H),1.34-1.30(m,2H).

[0276] LCMS m / z 443.20 [M] + .

[0277] Example 19

[0278] Compound 19: 6-((4-bromophenyl)(4-phenylcyclohexyl)amino)-N,N,N-trimethylhexane-1-ammonium chloride

[0279]

[0280] By replacing 3-1 in Example 3 with compound 19-1, and following the same synthesis method as compound 3, compound 19 was obtained, 55 mg, in 8% yield.

[0281] 1 H NMR (300MHz, CD3OD) δ7.83-7.65(m,4H),7.24-7.17(m,5H),3.37-3.28(m,2H),3.12(d,J=2.1Hz ,9H),3.11(s,2H),2.61-2.49(m,2H),2.08-1,97(m,2H),1.79-1,60(m,7H),1.57-1.60(m,7H).

[0282] LCMS m / z 471.20 [M] + .

[0283] Example 20

[0284] Compound 20: 5-((4-bromophenyl)(4-(3-fluorophenyl)cyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0285]

[0286] By replacing compounds 3-6 in Example 3 with compound 20-1, and following the synthesis method of compound 2, compound 20 was obtained, 55 mg, 37%.

[0287] 1H NMR (300MHz, CD3OD) δ7.42-7.20(m,3H),7.19-6.69(m,5H),3.29-2.19(m,2H),3.12(d,J=14.8Hz,9 H),3.08-2.88(m,2H),2.67-2.12(m,2H),1.97-1.78(m,4H),1.79-1.57(m,6H),1.55-1.23(m,4H).

[0288] LCMS m / z 475.20 [M] + .

[0289] Example 21

[0290] Compound 21: 5-((4-chlorophenyl)(4-phenylcyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0291]

[0292] By replacing compounds 3-4 in Example 3 with compound 21-1, and following the synthesis method of compound 2, compound 21 was obtained, 20 mg, in 7% yield.

[0293] 1 H NMR (300MHz, CD3OD) δ7.31-7.24(m,4H),7.22-7.13(m,2H),6.84-6.73(m,2H),3.29-3.21(m,2H),3.12(d,J=16.5Hz, 9H), 2.95 (br, 2H), 2.59-2.21 (m, 2H), 1.95 (d, J = 6.4Hz, 2H), 1.88-1.57 (m, 8H), 1.50-1.41 (m, 2H), 1.31-1.28 (m, 2H).

[0294] LCMS m / z 413.25 [M] + .

[0295] Example 22

[0296] Compound 22: 5-((4-cyclohexylphenyl)(4-phenylcyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0297]

[0298] By replacing compounds 3-4 in Example 3 with compound 22-1, and following the same synthesis method as compound 3, compound 22, 29 mg, was obtained in 9% yield.

[0299] 1H NMR (300MHz, CD3OD) δ7.59 (dd, J=14.2, 8.5Hz, 2H), 7.45 (dd, J=11.3, 8.5Hz, 2H), 7.36 (d ,J=7.4Hz,1H),7.21(ddd,J=15.0,12.7,4.6Hz,4H),3.88-3.60(m,3H),3.36-3.31(m,1H) ,3.28-3.22(m,1H),3.11(t,J=5.9Hz,9H),2.67-2.34(m,3H),2.22(brs,1H),2.12-1.97 (m,1H),1.96-1.79(m,6H),1.78-1.64(m,5H),1.57(d,J=10.4Hz,1H),1.55-1.12(m,9H).

[0300] LCMS m / z 461.30 [M] + .

[0301] Example 23

[0302] Compound 23: 5-((4-trifluoromethylphenyl)(4-phenylcyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0303]

[0304] By replacing compounds 3-4 in Example 3 with compound 23-1, and following the synthesis method of compound 3, compound 23, 15 mg, 5% was obtained.

[0305] 1 H NMR(300MHz,CD3OD)δ7.96(d,J=5.5Hz,3H),7.39(d,J=7.5Hz,1H),7.32-7.11(m,5H),3.95(s,1H),3.81(br,2H),3.38- 3.31(m,1H),3.11(d,J=5.8Hz,9H),2.95(s,1H),2.53(br,1H),2.08-1.92(m,2H),1.88-1.56(m,8H),1.51-1.33(m,4H).

[0306] LCMS m / z 447.25 [M] + .

[0307] Example 24

[0308] Compound 24: 5-((4-trifluoromethanesulfonylphenyl)(4-phenylcyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0309]

[0310] By replacing compounds 3-4 in Example 3 with compound 24-1, and following the same synthesis method as compound 3, compound 24 was obtained, 15 mg, in 10% yield.

[0311] 1 H NMR (300MHz, DMSO-d6) δ7.38-7.15 (m, 7H), 6.66 (t, J = 9.3Hz, 2H), 3.69 (s, 1H) ,3.19(s,4H),3.05(d,J=15.3Hz,9H),1.89-1.45(m,11H),1.33-1.18(m,4H).

[0312] LCMS m / z 511.26 [M] + .

[0313] Example 25

[0314] Compound 25: (R)-2-hydroxy-N,N,N-trimethyl-4-((4-phenylcyclohexyl)(4-(trifluoromethyl)phenyl)amino)butane-1-ammonium chloride

[0315]

[0316] By replacing compound 13-1 in Example 13 with compound 25-1, and following the synthetic methods of compounds 13 and 15, compound 25 was obtained.

[0317] 1 H NMR(300MHz,DMSO-d6)δ7.39-7.15(m,7H),6.63(t,J=9.6Hz,2H),4.55-4.41(m,1H),3.42-3 .15(m,5H),3.09(d,J=15.3Hz,9H),2.73-2.68(m,1H),1.84-1.54(m,8H),1.50-1.41(m,2H)

[0318] LCMS m / z 449.27 [M] + .

[0319] Example 26

[0320] Compound 26: 5-((4-bromophenyl)(4-(4-cyanophenyl)cyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0321]

[0322] By replacing compounds 3-6 in Example 33 with compound 26-1, and following the same synthetic method as compound 3, compound 26 was obtained.

[0323] 1 H NMR (400MHz, CD3OD) δ7.67(dd,J=16.3,8.3Hz,2H),7.59-7.42(m,2H),7.29(dd,J=15.5,9.0Hz,2H),6.87-6.70(m,2H),3.73-3.58(m,1H),3.36 (d,J=5.4Hz,2H),3.26(dd,J=13.3,5.8Hz,2H),3.15-3.07(m,9H),3.11 -3.05(m,1H),2.02-1.79(m,5H),1.76-1.59(m,6H),1.51-1.27(m,3H)..

[0324] LCMS m / z 482.21 [M] + .

[0325] Example 27

[0326] Compound 27: 5-((4-bromophenyl)(3-phenylcyclopentyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0327]

[0328] By replacing compounds 3-6 in Example 3 with compound 27-1, and following the same synthesis method as compound 3, compound 27 was obtained.

[0329] 1 H NMR(300MHz,CD3OD)δ7.44-7.16(m,7H),6.72(t,J=9.9Hz,2H),4.20(br,1H),3.68-3.59( m,2H),3.44-3.22(m,2H),3.10(d,J=12.6Hz,9H),2.80-2.77(m,1H),2.44-1.12(m,12H).

[0330] LCMS m / z 443.20 [M] + .

[0331] Example 28

[0332] Compound 28: 5-((4-trifluoromethoxyphenyl)(4-phenylcyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0333]

[0334] By replacing compounds 3-4 in Example 3 with compound 28-1, and following the same synthetic method as compound 3, compound 28 was obtained.

[0335] 1 H NMR(400MHz, CDCl3)δ7.34(d,J=4.3Hz,1H),7.30-7.16(m,4H),7.08(d,J=8.7Hz ,2H),6.81-6.65(m,2H),3.68-3.48(m,3H),3.41(d,J=19.2Hz,9H),3.24-3.15( m,1H),3.05-2.90(m,1H),2.60-2.15(m,1H),2.04-2.00(m,1H),1.96-1.90(m,1 H),1.83-1.74(m,3H),1.68-1.54(m,6H),1.49-1.40(m,2H),1.35-1.25(m,1H).

[0336] LCMS m / z 463.29 [M] + .

[0337] Example 29

[0338] Compound 29: 1-(5-((4-phenylcyclohexyl)(4-trifluoromethoxy)phenyl)amino)pentyl)-1-pyridine hydroiodate

[0339]

[0340] By replacing 3-4 in Example 3 with compound 29-1 and replacing 3-2 in Example 3 with compound 29-2, and following the same synthesis method as compound 3, compound 29 was obtained, 38 mg, in a yield of 33%.

[0341] 1 H NMR(300MHz,DMSO-d6)δ8.91-8.72(m,3H),8.24-8.19(m,2H),7.38-7.13(m,7H),6.68(t ,J=9.9Hz,2H),3.68(br,1H),3.22-3.11(m,4H),1.90-1.45(m,11H),1.34-1.16(m,4H).

[0342] LCMS m / z 483.26 [M] + .

[0343] Example 30

[0344] Compound 30: 4-(5-((4-phenylcyclohexyl)(4-(trifluoromethoxy)phenyl)amino)pentyl)-4-methylmorpholine hydroiodate

[0345]

[0346] Compound 30 was obtained by replacing 3-4 in Example 3 with compound 30-1 and replacing 3-2 in Example 3 with compound 30-2, and by following the same synthesis method as compound 3.

[0347] 1 H NMR (300MHz, DMSO-d6) δ7.39-7.11(m,7H),6.72(d,J=9.0Hz,2H),3.81-3.75(m,4H),3.68-3.48(m,3H),3.44-3.11(m, 8H),3.05-2.94(m,1H),2.61-2.16(m,1H),2.04-2.00(m,1H),1.95-1.71(m,4H),1.68-1.54(m,6H),1.49-1.15(m,3H).

[0348] LCMS m / z 505.30 [M] + .

[0349] Example 31

[0350] Compound 31: 1-(5-((4-phenylcyclohexyl)(4-(trifluoromethoxy)phenyl)amino)pentyl)1-methylpiperidine hydroiodate

[0351]

[0352] Compound 31 was obtained by replacing 3-4 in Example 3 with compound 31-1 and replacing 3-2 in Example 3 with compound 31-2, and by following the synthesis method of compound 3.

[0353] 1 H NMR (300MHz, DMSO-d6) δ7.35-7.16(m,5H),7.07(d,J=9.0Hz,2H),6.72(d,J=9.0Hz,2H),3.68-3.48(m,3H),3.41-3.23(m,7H),3.2 1-3.13(m,1H),3.06-2.94(m,1H),2.43-2.05(m,2H),2.00-1.90(m,3H),1.86-1.74(m,6H),1.68-1.54(m,6H),1.49-1.29(m,4H).

[0354] LCMS m / z 503.31 [M] + .

[0355] Example 32

[0356] Compound 32: 1-(5-((4-phenylcyclohexyl)(4-(trifluoromethoxy)phenyl)amino)pentyl)-1-methyl-pyrrolidine hydroiodate

[0357]

[0358] Compound 32 was obtained by replacing 3-4 in Example 3 with compound 32-1 and replacing 3-2 in Example 3 with compound 32-2, and by following the same synthesis method as compound 3.

[0359] 1 H NMR (300MHz, DMSO-d6) δ7.35-7.18(m,5H),7.08(d,J=9.0Hz,2H),6.73(d,J=9.0Hz,2H),3.68-3.48(m,3H),3.41-3.23(m,7H),3.2 2-3.13(m,1H),3.06-2.91(m,1H),2.53-2.05(m,3H),2.00-1.90(m,4H),1.86-1.74(m,2H),1.68-1.54(m,6H),1.49-1.29(m,4H).

[0360] LCMS m / z 489.31 [M] + .

[0361] Example 33

[0362] Compound 33: 5-((3-fluoro-4-(trifluoromethyl)phenyl)(4-phenylcyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0363]

[0364] By replacing compounds 3-4 in Example 3 with compound 33-1, and following the same synthetic method as compound 3, compound 33 was obtained.

[0365] 1H NMR (300MHz, DMSO-d6) δ7.95(d,J=5.4Hz,1H),7.62(d,J=5.4Hz,1H),7.38(d,J=7.2Hz,1H),7.31-7.11(m,5H),3.96(s,1H),3.80(br ,2H),3.39-3.31(m,1H),3.11(d,J=5.8Hz,9H),2.96(s,1H),2.52(br,1H),2.10-1.95(m,2H),1.89-1.56(m,8H),1.52-1.33(m,4H).

[0366] LCMS m / z 466.28 [M+H] + .

[0367] Example 34

[0368] Compound 34: 5-((4-phenylcyclohexyl)(6-(trifluoromethyl)pyridin-3-yl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0369]

[0370] By replacing compounds 3-4 in Example 3 with compound 34-1, and following the same synthetic method as compound 3, compound 34 was obtained.

[0371] 1 H NMR (300MHz, DMSO-d6) δ8.02(d,J=7.2Hz,1H),7.85(d,J=3.3Hz,1H),7.53(d,J=3.3Hz,1H),7.32-7.12(m,5H),3.97(br,1H),3.79(b r,2H),3.38-3.30(m,1H),3.11(d,J=5.8Hz,9H),2.95(s,1H),2.51(br,1H),2.11-1.96(m,2H),1.88-1.53(m,8H),1.52-1.33(m,4H).

[0372] LCMS m / z 448.29 [M+H] + .

[0373] Example 35

[0374] Compound 35: 6-((4-phenylcyclohexyl)(4-(trifluoromethoxy)phenyl)amino)-N,N,N-trimethylhexane-1-ammonium chloride

[0375]

[0376] Compound 35 was obtained by replacing 3-4 in Example 3 with compound 35-1 and 3-1 in Example 3 with compound 35-2, and by following the same synthetic method as compound 3.

[0377] 1 H NMR (300MHz, CDCl3) δ7.37-7.27(m,2H),7.25-7.15(m,3H),7.08(d,J=8.7Hz,2H),6.70(d,J=8.7Hz,2H),3.71-3.52(m,3H), 3.42(s,9H),3.19(t,J=7.2Hz,2H),2.61-2.51(m,1H),2.08-1.89(m,4H),1.78(s,2H),1.69-1.51(m,6H),1.51-1.38(m,4H).

[0378] LCMS m / z 477.31 [M] + .

[0379] Example 36

[0380] Compound 36: 7-((4-phenylcyclohexyl)(4-(trifluoromethoxy)phenyl)amino)-N,N,N-trimethylheptane-1-ammonium chloride

[0381]

[0382] Compound 36 was obtained by replacing 3-4 in Example 3 with compound 36-1 and 3-1 in Example 3 with compound 36-2, and by following the same synthesis method as compound 3.

[0383] 1 H NMR (300MHz, CDCl3) δ7.40-7.27(m,3H),7.26-7.18(m,2H),7.08(d,J=8.7Hz,2H),6.78-6.64(m,2H),3.68-3.53(m,3H),3.44(d,J= 7.2Hz,9H),3.18(t,J=7.8Hz,1H),3.06-2.93(m,1H),2.61-2.19(m,1H),,2.10-1.89(m,3H),1.84-1.52(m,9H),1.46-1.30(m,6H).

[0384] LCMS m / z 491.31 [M] + .

[0385] Example 37

[0386] Compound 37: 5-((4-phenylcyclohexyl)(4-(trifluoromethoxy)phenyl)amino)-N,N,N-triethylpentane-1-ammonium chloride

[0387]

[0388] Compound 37 was obtained by replacing 3-4 in Example 3 with compound 37-1 and replacing 3-2 in Example 3 with compound 37-2, and by following the synthesis method of compound 3.

[0389] 1 H NMR (400MHz, CDCl3) δ7.34-7.16(m,5H),7.08(d,J=8.7Hz,2H),6.81-6.65(m,2H),3.63(s,1H),3.38-3.19(m,9H),3.08 -2.94(m,2H),2.51(s,br,1H),2.21(s,br,1H),1.92(s,br,3H),1.75-1.59(m,7H),1.46(s,br,2H),1.34-1.17(m,9H).

[0390] LCMS m / z 505.29 [M] + .

[0391] Example 38

[0392] Compound 38: 6-((4-phenylcyclohexyl)(4-(trifluoromethoxy)phenyl)amino)-N,N,N-triethylhexane-1-ammonium chloride

[0393]

[0394] Compound 38 was obtained by replacing 3-4 in Example 3 with compound 38-1, 3-1 in Example 3 with compound 38-2, and 3-2 in Example 3 with compound 38-3, using the same synthetic method as compound 3.

[0395] 1 H NMR (300MHz, CDCl3) δ7.36-7.26(m,3H),7.23-7.15(m,2H),7.06(d,J=8.6Hz,2H),6.80-6.57(m,2H),3.57-3.39 (m,6H),3.29-2.90(m,5H),2.53(s,1H),2.20(s,1H),2.03-1.90(m,2H),1.72-1.49(m,6H),1.48-1.18(m,16H).

[0396] LCMS m / z 519.32 [M] + .

[0397] Example 39

[0398] Compound 39: 5-((5Z,8Z,11Z,14Z,17Z)-N-(4-bromophenyl)eicosico-5,8,11,14,17-pentenoylamino)-N,N,N-trimethylpentane-1-ammonium chloride

[0399]

[0400] Synthesis route:

[0401]

[0402] Step a: Weigh all-cis-eicosapentaenoic acid (1.00 g, 3.31 mmol), 4-bromoaniline (568 mg, 3.31 mmol), DIEA (2.32 g, 9.93 mmol), and PyBOP (2.00 g, 4.96 mmol) into a round-bottom flask. Add 20 mL of LDCM to the reaction flask and react at room temperature for 12 h. Add water to the reaction mixture, extract with EA, combine the organic phases, wash with saturated brine, concentrate under reduced pressure, and purify by silica gel column chromatography. Elute with PE-EA (20:1) to obtain (5 Z, 8 Z, 11 Z, 14 Z, 17 Z)-N-(4-bromophenyl)-all-cis-eicosapentaenoic acid (300 mg, 19%). This was used directly in the next synthesis.

[0403] Step b: Weigh (5 Z, 8 Z, 11 Z, 14 Z, 17 Z)-N-(4-bromophenyl)-cis-tetraenoenamide (455 mg, 1.0 mmol) and sodium hydroxide (80 mg, 2.0 mmol) and dissolve them in 5 mL of DMF. Stir at room temperature for 30 min under nitrogen protection. Weigh 5-bromo-N,N,N-trimethylpentane-1-ammonium bromide (347 mg, 1.2 mmol) and add it to the reaction solution. Continue stirring at room temperature for 2 h. Dilute the reaction solution with 50 mL of water, extract with EA, wash the organic phase with saturated brine, concentrate under reduced pressure, and purify by silica gel column chromatography. Elute with DCM-MeOH (20:1-4:1) to obtain crude compound 4. Further purification by preparative HPLC (C18 silica gel bonded phase) yields compound 39 (13.5 mg, 2%).

[0404] 1H NMR (300MHz, CD3OD) δ7.64(d,J=8.0Hz,2H),7.20(d,J=5.3Hz,2H),6.50-5.10(m,8H),3.72(t,J=7.3H z, 2H), 3.59-3.50 (m, 1H), 3.27 (s, 2H), 3.10 (d, J = 1.4Hz, 9H), 2.91-2.57 (m, 3H), 2.32-0.71 (m, 23H).

[0405] LCMS m / z 583.35 [M] + .

[0406] Example 40

[0407] Compound 40: 5-((4-bromobenzyl)(4-phenylcyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium bromide

[0408]

[0409] By replacing compounds 3-4 in Example 3 with compound 40-1, and following the same synthetic method as compound 3, compound 40 was obtained, yielding 129 mg, 44%

[0410] 1 H NMR (300MHz, CD3OD) δ7.68 (d, J=8.5Hz, 2H), 7.59 (d, J=8.5Hz, 2H), 7.33-7. 11(m,5H),4.56(d,J=13.4Hz,1H),4.34(d,J=13.5Hz,1H),3.51(t,J=11.8H z,1H),3.44-3.31(m,3H),3.17(d,J=13.6Hz,10H),2.64(t,J=12.3Hz,1H), 2.30(s,2H),2.06(d,J=13.2Hz,2H),1.91-1.69(m,8H),1.47-1.32(m,2H).

[0411] LCMS m / z 471.25 [M+H] + .

[0412] Example 41

[0413] Compound 41: 5-(di(4-phenylcyclohexyl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0414]

[0415] By replacing compounds 3-4 in Example 3 with compound 41-1, and following the same synthetic method as compound 3, compound 41 was obtained.

[0416] 1 H NMR (300MHz, DMSO-d6) δ7.39-7.19(m,10H),3.19-3.11(m,4H),3.05(d,J=14.9Hz, 9H),2.77-2.72(m,2H),2.62-2.55(m,2H),1.90-1.45(m,18H),1.35-1.15(m,4H).

[0417] LCMS m / z 461.38 [M+H] + .

[0418] Example 42

[0419] Compound 42: 5-((4-chlorophenyl)(4-chlorophenyl)amino)-N,N,N-trimethylpentane-1-ammonium bromide

[0420]

[0421] By replacing compounds 3-4 in Example 3 with compound 42-1, and replacing compounds 3-6 in Example 3 with compound 42-2, and following the same synthetic method as compound 3, compound 42 was obtained, yielding 82 mg of compound 42 in 54% yield.

[0422] 1 H NMR (300MHz, CD3OD) δ8.49 (s, 1H), 7.31-7.25 (m, 2H), 7.18 (d, J = 8.7Hz, 2H), 7.12-7.03 (m, 2H), 6.69-6.60 (m, 2H), 4. 52(s,2H),3.48-3.39(m,2H),3.33(s,1H),3.27(s,1H),3.10(s,9H),1.87-1.60(m,4H),1.40(dt,J=15.2,7.7Hz,2H).

[0423] LCMS m / z 379.10 [M] + .

[0424] Example 43

[0425] Compound 43: 5-((4-bromophenyl)((5Z,8Z,11Z,14Z,17Z)-eicos-5,8,11,14,17-penten-1-yl)amino)-N,N,N-trimethylpentane-1-ammonium chloride

[0426]

[0427] By replacing compounds 3-6 in Example 3 with compound 43-1, and following the same synthetic method as compound 3, compound 43 was obtained, 12 mg, in 15% yield.

[0428] 1 H NMR(300MHz,CD3OD)δ7.64(d,J=8.0Hz,2H),7.20(d,J=5.3Hz,2H),6.50-5.10(m,10H),3.78- 3.69(m,4H),3.59-3.50(m,2H),3.10(d,J=1.4Hz,9H),2.91-2.57(m,8H),2.32-0.71(m,17H).

[0429] LCMS m / z 569.34 [M] + .

[0430] Example 44

[0431] Compound 44: 5-(6-bromo-3-phenyl-1,2,3,4-tetrahydro-9H-carbazole-9-yl)-N,N,N-trimethylpentane-1-ammonium bromide

[0432]

[0433] Synthesis route:

[0434]

[0435] Step a: Weigh 200 mg (1.1 mmol) of 4-bromophenylhydrazine and dissolve it in 2 mL of acetic acid. Weigh 225 mg (1.3 mmol) of 4-phenylcyclohexanone and add it to the reaction solution. Heat the reaction solution to 100 °C and react for 16 h. Cool down, concentrate the reaction solution under reduced pressure, and then purify it by silica gel column chromatography. Elute with PE-EA (5:1) to obtain compound 6-bromo-3-phenyl-2,3,4,9-tetrahydro-1H-carbazole (120 mg, 40%).

[0436] Step b: Weigh 6-bromo-3-phenyl-2,3,4,9-tetrahydro-1H-carbazole (60 mg, 0.2 mmol), 5-bromo-N,N,N-trimethylpentane-1-ammonium bromide (64 mg, 0.2 mmol), and cesium carbonate (117 mg, 0.4 mmol) and mix them in 1 mL of MeOH. Heat to 70 °C and react for 2 h. Cool down, quench the reaction mixture with water, extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then perform preparative HPLC (C10-C20). 18 The compound was purified by bonding silica gel and eluted with MeOH:H2O (50%) to give compound 44 (28 mg, 33%).

[0437] 1 H NMR (300MHz, CD3OD) δ7.49(d,J=1.8Hz,1H),7.30(dd,J=4.5,3.7Hz,4H),7.26(d,J=3.3Hz,1H),7.23-7.13(m,2H),4.13(t, J=6.9Hz,2H),3.26-3.20(m,2H),3.05(s,9H),2.99-2.69(m,5H),2.27-2.05(m,2H),1.89-1.65(m,4H),1.39-1.28(m,2H).

[0438] LCMS m / z 453.15 [M] + .

[0439] Example 45

[0440] Compound 45: 5-(6-bromo-3-(4-cyanophenyl)-1,2,3,4-tetrahydro-9H-carbazole-9-yl)-N,N,N-trimethylpentane-1-ammonium bromide

[0441]

[0442] By replacing 44-2 in Example 44 with compound 45-1, and following the same synthetic method as compound 44, compound 45 was obtained.

[0443] 1 H NMR(300MHz,CD3OD)δ7.75(d,J=3.3Hz,2H),7.49(s,1H),7.38-7.16(m,4H),4.11(t,J=6.9Hz,2H),3.28 -3.20(m,2H),3.01(s,9H),3.00-2.61(m,7H),2.22-2.03(m,2H),1.90-1.66(m,2H),1.39-1.28(m,2H).

[0444] LCMS m / z 478.18 [M+H] + .

[0445] Example 46

[0446] Compound 46: 5-(7-bromo-2-phenyl-2,3-dihydrocyclopentano[b]indole-4(1H))-N,N,N-trimethylpentane-1-ammonium bromide

[0447]

[0448] By replacing 44-2 in Example 44 with compound 46-1, and following the same synthetic method as compound 44, compound 46 was obtained.

[0449] 1 H NMR (300MHz, CD3OD) δ7.53(d,J=1.8Hz,1H),7.28(dd,J=4.5,3.7Hz,4H),7.24(d,J=3.3Hz,1H),7.22-7.11(m,2H),4.10(t, J=6.9Hz,2H),3.28-3.20(m,2H),3.06(s,9H),2.99-2.69(m,5H),2.20-2.01(m,2H),1.89-1.65(m,2H),1.40-1.29(m,2H).

[0450] LCMS m / z 439.17 [M+H] + .

[0451] Example 47

[0452] Compound 47: 5-(6-trifluoromethoxy-3-phenyl-1,2,3,4-tetrahydro-9H-carbazole-9-yl)-N,N,N-trimethylpentane-1-ammonium bromide

[0453]

[0454] By replacing 44-1 in Example 44 with compound 47-1, and following the same synthesis method as compound 44, compound 47 was obtained.

[0455] 1 H NMR (300MHz, CD3OD) δ7.69(d,J=1.8Hz,1H),7.45(d,J=3.6Hz,1H),7.29(dd,J=4.5,3.6Hz,4H),7.24(d,J=3.3Hz,1H),6.93(d,J=3.6Hz, 1H), 4.11 (t, J = 6.9Hz, 2H), 3.24-3.19 (m, 2H), 3.06 (s, 9H), 2.99-2.67 (m, 5H), 2.26-2.05 (m, 2H), 1.90-1.65 (m, 4H), 1.38-1.28 (m, 2H).

[0456] LCMS m / z 459.19 [M+H] + .

[0457] Test Example 1. MTT assay to detect the effect of a compound on the proliferation of 3T3-L1 preadipocytes

[0458] The MTT assay was used. 3T3-L1 preadipocytes were seeded in 48-well cell culture plates. When the cells reached 80% confluence, the test compound was added to a final concentration of 20 μM. A solvent control group was also included. Six parallel wells were used for each drug concentration. After 48 hours of drug treatment, 20 μL of MTT (0.5 mg / mL) solution was added to each well, and the cells were cultured for another 4 hours. The MTT solution was discarded, and 270 μL of Formazan dissolving solution was added to each well to fully dissolve the crystals. The absorbance was measured at 570 nm using a microplate reader. Cell viability (%) = (average OD of treated cells / average OD of solvent control cells) × 100%.

[0459] The results are shown in Table 1. The compounds of the present invention did not significantly inhibit the proliferation of 3T3-L1 precursor adipocytes.

[0460] Table 1. Inhibitory effects of compounds on the proliferation of 3T3-L1 precursor adipocytes.

[0461]

[0462] Test Example 2. MTT assay to detect the effect of a compound on the proliferation of 3T3-L1 adipocytes during differentiation.

[0463] The MTT assay was used. 3T3-L1 preadipocytes were seeded in 48-well cell culture plates. After reaching 80% confluence, the cells were cultured for two more days. Then, 200 μL of DMEM / F12 (10% FBS) medium containing a differentiation cocktail and the test compound at a final concentration of 10 μM were added. A solvent control group was also included. Six parallel wells were used for each drug concentration. After 48 hours of culture, 20 μL of MTT (0.5 mg / mL) solution was added to each well, and the cells were cultured for another 4 hours. The MTT solution was discarded, and 270 μL of Formazan dissolving solution was added to each well to fully dissolve the crystals. The absorbance was measured at 570 nm using a microplate reader. Cell viability (%) = (average OD of treated cells / average OD of solvent control cells) × 100%.

[0464] The results are shown in Table 2. After 48 hours of treatment, compound 11 significantly inhibited the proliferative activity of adipocytes in the 3T3-L1 differentiation process.

[0465] Table 2. Inhibitory effects of compounds on adipocyte proliferation during 3T3-L1 differentiation.

[0466]

[0467] Cell viability: A: Below 20%, B: 20-60%, C: 60-80%, D: 80-100%

[0468] Classification

[0469] Test Example 3. MTT assay to detect the effect of a compound on the proliferation of 3T3-L1 mature adipocytes

[0470] The MTT assay was used. 3T3-L1 preadipocytes were seeded in 48-well cell culture plates. After the cells reached complete contact, they were cultured for two more days, then in DMEM / F12 (10% FBS) medium containing differentiation cocktail for three days. This was followed by maintenance medium for four days, with fresh maintenance medium added every two days. On day seven, the test compound was added to a final concentration of 20 μM. A solvent control group was also included. Six parallel wells were used for each drug concentration. After 48 hours of drug treatment, 20 μL of MTT (0.5 mg / mL) solution was added to each well, and the cells were cultured for another 4 hours. The MTT solution was discarded, and 270 μL of Formazan dissolving solution was added to each well to fully dissolve the crystals. The absorbance was measured at 570 nm using a microplate reader. Cell viability (%) = (average OD of treated cells / average OD of solvent control cells) × 100%.

[0471] The results are shown in Table 3. After 48 h of treatment on mature adipocytes, compounds 1, 3, 11, 35, 37 and 44 significantly inhibited the proliferation activity of 3T3-L1 mature adipocytes, which was superior to the positive control drug sodium deoxycholate.

[0472] Table 3. Inhibitory effects of compounds on the proliferation of 3T3-L1 mature adipocytes.

[0473]

[0474]

[0475]

[0476] Note: Cell viability grading: A: below 20%, B: 20-60%, C: 60-80%, D: 80-100%

[0477] Test Example 4: Intraperitoneal (ip) injection of compound 11 into high-fat, high-sugar fed rats

[0478] Male SD rats, weighing 190±10g, were used. Hulling conditions included a temperature of 22±2℃, humidity of 40-70%, a 12-hour light / dark cycle, and a high-fat, high-sugar diet with daily changes. Free access to food and water was provided. Rats were divided into groups of 20 rats (n=30) to administer the drug when they reached a weight of 300±20g. The groups included a negative control and high, medium, and low dose test groups of compound 11, with 5 rats in each group.

[0479] Preparation method: Weigh 50.00 mg of compound 11 and dissolve it in 0.5 ml of Solutol HS15 by sonication. After complete sonication dissolution, add 4.5 ml of physiological saline and continue sonication until complete dissolution, to obtain a final concentration of 10 mg / ml.

[0480] Dosage regimen: Single intraperitoneal injection

[0481] The specific grouping information and dosing regimen are as follows:

[0482] Table 4 Grouping and Dosing Regimens

[0483]

[0484] Results: After a single intraperitoneal injection of compound 11, rats were observed for 7 days, and their body weight was measured on day 7. The results are as follows... Figure 1 As shown, compared with the negative control group, each dose group of compound 11 significantly inhibited the weight gain of rats in a dose-dependent manner. The rats in each dose group were in good condition and had good vitality, similar to the negative control. No abnormalities were found in the organs of the rats in each dose group after dissection.

[0485] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof: A1 is selected from the following group: C3-C8 cycloalkyl, C6-C10 aryl, 5-10 heteroaryl; A2 is selected from the following group: chemical bonds, saturated or partially unsaturated C3-C8 carbon rings, C3-C8 cycloalkyl groups, C6-C10 aryl groups, 5-10 heteroaryl groups, and C14-C24 saturated or unsaturated alkyl groups; V is selected from the group consisting of: chemical bonds, substituted or unsubstituted C1-C6 alkylene groups, substituted or unsubstituted C3-C8 cycloalkyl groups, and substituted or unsubstituted 3-8 membered heterocyclic groups; the substitution refers to having one or more substituents selected from the group consisting of: deuterium, halogen, amino, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy. W is selected from the group consisting of: chemical bonds, substituted or unsubstituted C1-C6 alkylene groups, substituted or unsubstituted saturated or partially unsaturated C3-C8 carbocyclic rings, substituted or unsubstituted 3-8 membered heterocyclic groups, and carbonyl groups; the substitution refers to having one or more substituents selected from the group consisting of: deuterium, halogen, amino, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy. X is selected from the group consisting of N, P, and P=O; preferably, X is N. L represents the linking group -(CH2). j -, the -(CH2) j One or more methylene groups in - are optionally selected from -NR 3’ -, -O-, -S-, -S(O)-, -S(O)NR 3’ -、-NR 3’ S(O)-, -S(O)2-, -S(O)2NR 3’ -、-NR 3’ S(O)2-、-NR 4’ S(O)2NR 3’ -、-CR 1’ R 2’ -, -C(O)-, -C(O)O-, -OC(O)-, -NR 3’ C(O)O-、-OC(O)NR 3’ -、-C(O)NR 3’ -、-NR 3’ C(O)-、-NR 4’ C(O)NR 3’ -, -P(O)-, -P(O)O-, -OP(O)-, -OP(O)O-, vinylene, ethynylene, C3-C12 cycloalkylene, or a group containing one or more 3-12-membered heteroalkylene groups selected from N, O, or S heteroatoms; wherein the methylene, vinylene, cycloalkylene, or heteroalkylene group is each optionally and independently substituted by one or more substituents selected from the group consisting of: halogen, -OR 3’ -NR 3’ R 4’ Oxylated, nitro, cyano, C1-C6 alkyl, -S(C1-C6 alkyl), C3-C10 cycloalkyl, 3-10 heterocyclic alkyl, -C(O)R 1’ -C(O)OR 3’ -OC(O)R 1’ -C(O)NR 3’ -NR 3’ C(O)R 1’ -S(O)R 1’ -S(O)NR 3’ -S(O)2R 1’ -S(O)2NR 3’ -NR 3’ S(O)2R 1’ -NR 4’ S(O)2NR 3’ -OC(O)NR 3’ -NR 4’ C(O)NR 3’ ;R 1’ R 2’ Each can be independently a halogen, -OH, or -NR. 3’ R 4’ C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C10 cycloalkyl, -O(C3-C10 cycloalkyl), -NH(C3-C10 cycloalkyl), 3-10 membered heterocyclic alkyl, -O(3-10 membered heterocyclic alkyl), -NH(3-10 membered heterocyclic alkyl), R 3’ R 4’ Each is independently hydrogen, deuterium, C1-C6 alkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclic alkyl; j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R1 is selected from the group consisting of: absent, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted benzene ring, substituted or unsubstituted 5-10 heteroaryl, wherein the substitution refers to having one or more substituents selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkylamino. R2 is selected from the group consisting of: absent, halogen, cyano, trifluoromethanesulfonyl, nitro, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino (C1-C6 alkyl), substituted or unsubstituted N (C1-C6 alkyl)2, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic, substituted or unsubstituted C6-C10 aryl (preferably phenyl); the substitution refers to having one or more substituents selected from the group consisting of: deuterium, halogen, amino, hydroxyl, cyano, C1-C6 alkyl; a and b can each independently be 0, 1, 2, 3, 4, 5 or 6; Y is independently selected from the following group: R4 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl groups, and R4 together with the nitrogen attached thereto form substituted or unsubstituted 4- to 7-membered heterocyclic groups; R5 is selected from the following group: hydrogen, substituted or unsubstituted C1-C6 alkyl groups, or... Z - Anions that do not exist or are selected from the following group of acids: inorganic acids, organic acids, and amino acids; This indicates that the bond is absent or covalent; When V and W are chemical bonds and A2 is a partially unsaturated C3-C8 carbon ring, The ring atoms in A1 and A2 that are covalently bonded and connected to X, along with their adjacent ring atoms, together with X, form a 5-membered heteroaromatic ring.

2. The compound of claim 1, wherein the compound is a compound of formula (II): R1, R2, A1, A2, V, W, L, Y, a, b are as defined in claim 1.

3. The compound of claim 1, wherein the compound is a compound of formula (III): Ring B is selected from the following group: substituted or unsubstituted C3-C8 carbocyclic groups, substituted or unsubstituted 3-8 membered heterocyclic groups; R1, R2, L, and Y are as defined in claim 1.

4. The compound of claim 2, wherein, The compound is the compound represented by formula (IV): R1, R2, V, W, L, Y, a, b are as defined in claim 2.

5. The compound of claim 1, wherein, V is selected from the following group: chemical bond, C1-C3 alkylene group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group, carbonyl group.

6. The compound of claim 1, wherein, W is selected from the group consisting of: chemical bond, substituted or unsubstituted C1-C3 alkylene group, substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted 3-7 membered heterocyclic group, carbonyl group; the substitution refers to having one or more substituents selected from the group consisting of: deuterium, halogen, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy.

7. The compound of claim 1, wherein, W is selected from the following group: chemical bonds, Indicates a single or double bond; L is selected from: -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-; wherein one or more H groups in the methylene group are optionally substituted by one or more substituents selected from the group consisting of: halogen, amino, hydroxyl; Y is selected from:

8. The compound of claim 1, wherein, The compounds are selected from the group consisting of:

9. A pharmaceutical composition comprising the compound of any one of claims 1-8 or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and a pharmaceutically acceptable carrier.

10. Use of the compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for reducing localized fat and body weight in a subject.

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