Tricyclic compounds, compositions comprising same and uses thereof

Abstract

A compound of the present invention, which is a tricyclic derivative represented by chemical formula 1 or a pharmaceutically acceptable salt thereof, has an excellent inhibitory effect on serotonin activity and a pharmaceutical composition comprising same can be thus advantageously used for preventing or treating a metabolic disease associated with serotonin activation, etc.

Description

Tricyclic compounds and their pharmaceutical uses

[0001] The present invention relates to tricyclic compounds that act as serotonin antagonists and their pharmaceutical use for treating metabolic diseases and the like. More specifically, the present invention relates to tricyclic compounds that act as serotonin 2A antagonists and their pharmaceutical use for treating obesity, fatty liver disease, steatohepatitis, and the like.

[0002] Obesity is a condition characterized by excessive accumulation of body fat. Obesity occurs when calories consumed are less than burned, resulting in the accumulation of excess energy in the form of body fat. Causes of obesity include irregular eating habits, excessive food intake, lack of exercise, genetics, and psychological factors. In addition to shortness of breath and joint pain, obesity can also lead to cardiovascular disease, high blood pressure, sleep apnea, dyslipidemia, hyperinsulinemia, and osteoarthritis.

[0003] The goal of obesity treatment is to prevent and treat obesity-related complications. The most basic treatment for obesity involves lifestyle changes, while pharmacological treatment primarily involves appetite suppressants. However, because these appetite suppressants act on the central nervous system, they can have side effects, including mental illnesses like depression.

[0004] Appetite suppressants regulate serotonin (5-HT) in the central nervous system, a neurotransmitter that regulates mood, sleep, and appetite. Serotonin acts not only in the central nervous system but also in peripheral tissues, where it has been reported to play a crucial role in metabolic regulation. Because serotonin cannot cross the blood-brain barrier, serotonin in the central nervous system and peripheral tissues is considered to operate independently.

[0005] It is known that inhibition of serotonin synthesis in peripheral tissues reduces lipogenesis in white adipocytes and burns energy by generating heat in brown adipocytes (Oh C et al., Nature Communication 6, 6794, 2015).

[0006] Meanwhile, fatty liver disease is a disease that occurs when excessive fat accumulates in liver cells, increasing the fat content of the liver. Fatty liver disease is broadly divided into alcoholic fatty liver disease and non-alcoholic fatty liver disease. Excessive alcohol consumption leads to the accumulation of fat in liver cells, and alcohol metabolites damage liver cells. However, non-alcoholic fatty liver disease refers to a condition in which fat accumulates in the liver despite no or minimal alcohol consumption.

[0007] Fatty liver disease encompasses a variety of liver diseases, ranging from simple fatty liver disease, which involves only fat accumulation without liver cell damage, to steatohepatitis, which causes persistent liver cell damage, and to cirrhosis, which is accompanied by symptoms such as ascites and jaundice. Fatty liver disease is characterized by the accumulation of neutral fat within hepatocytes, and the resulting triglyceride vesicles increase in size over time. These fat vesicles increase the inflammatory response, leading to hepatitis or liver fibrosis.

[0008] Treatments for fatty liver disease include weight loss through diet and exercise. Antidiabetic medications that improve insulin resistance are used for short-term treatment. However, these are short-term treatments, and long-term efficacy has not been reported to date. Furthermore, commercially available lipid-lowering and liver-protecting medications are only effective for preservation, not treatment.

[0009] A recent study showed that serotonin antagonists inhibited the proliferation of damaged hepatocytes and increased the rate of apoptosis when treated with liver-damaged rats (Ruddell et al., The American Journal of Pathology, 11 (1), 52-58, 2011). In addition, treatment with serotonin receptor inhibitors ketanserin and sarpogrelate decreased the viability of liver-damaged LX-2 cells and induced apoptosis (Kim et al., Liver International, 33 (4), 535-543, 2013). In addition, liver-specific knockout mice of serotonin receptor 2A (HTR2A) were generated, and improvements in hepatic steatosis and reductions in genes related to inflammation and fibrosis were confirmed (Choi et al., Nat. Commun. 9, 4828, 2018).

[0010] [Prior Art Literature]

[0011] (Non-patent literature 1) Oh C et al., Nature Communication 6, 6794, 2015

[0012] (Non-patent literature 2) Ruddell et al., The Amer. J. Patho., 11 (1), 52-58, 2011

[0013] (Non-patent literature 3) Kim et al., Liver International, 33 (4), 535-543, 2013

[0014] (Non-patent document 4) Choi et al., Nat. Commun. 9, 4828, 2018

[0015] In order to treat obesity, it is important to suppress the synthesis of serotonin in the peripheral nervous system. Accordingly, the inventors of the present invention tried to find serotonin receptors associated with obesity in peripheral tissues and found that serotonin 2A (5-HT) 2A ) receptor expression was confirmed to increase in an obese state. In addition, it was confirmed that knocking out the serotonin 2A receptor could reduce body weight and improve fatty liver (salt) and liver fibrosis.

[0016] Accordingly, the present invention seeks to provide a compound that acts as a serotonin antagonist and its pharmaceutical use for diseases associated with serotonin activation.

[0017] Accordingly, the present invention provides a compound which is a tricyclic derivative represented by chemical formula 1, a pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

[0018] In addition, the present invention provides a pharmaceutical composition for preventing or treating a disease related to serotonin activation, comprising the compound according to the present invention as an active ingredient.

[0019] The tricyclic derivative, pharmaceutically acceptable salt, stereoisomer or prodrug thereof according to the present invention can exhibit an excellent antagonistic effect against serotonin, particularly serotonin 2A.

[0020] Therefore, the compound according to the present invention can be usefully used for the prevention or treatment of diseases related to serotonin activation, such as metabolic diseases such as obesity and fatty liver (salt).

[0021] The present invention is described in detail below.

[0022] In this specification, the term “halogen” means F, Cl, Br or I unless otherwise stated.

[0023] The term "alkyl", unless otherwise specified, means a linear or branched saturated hydrocarbon residue. For example, "C1-10 "Alkyl" means an alkyl group having a skeleton of 1 to 10 carbons. Specifically, C 1-10 Alkyl can be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.

[0024] The term "alkoxy", unless otherwise specified, means a linear or branched alkyl-oxy moiety. For example, "C 1-6 "Alkoxy" means alkyl-oxy with a skeleton of 1 to 6 carbons. Specifically, C 1-6 Alkoxy may include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentoxy, i-pentoxy, t-pentoxy, sec-pentoxy, neopentoxy, hexyloxy, and the like.

[0025] The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy substituted with one or more halogens. Specifically, a haloalkyl or haloalkoxy may be an alkyl or alkoxy substituted with one or more halogens, either homologous or heterologous.

[0026] The term "cycloalkyl" refers to a saturated monocycle or polycycle containing only carbon atoms in the ring. A cycloalkyl may have from three to seven carbon atoms, for example, as a monocycle.

[0027] The present invention, in one aspect, provides a compound which is a tricyclic derivative represented by the following chemical formula 1, a pharmaceutically acceptable salt, stereoisomer or prodrug thereof:

[0028] [Chemical Formula 1]

[0029]

[0030] In the above formula

[0031] X is H, halogen, C 1-6 Alkyl, or C 1-6 It is alkoxy;

[0032] R is H, C 1-10 Alkyl, -A, -L 1 -R 1 , -L 1 -A, -L 1 -L 2 -A, or -L 1 -L 2 -L 3 -A and;

[0033] L 1 Silver -(CH2) n -, -C(=O)-, -C(=O)-O-, -CH(-OH)-CH2-, -S(=O)2-, or -C(=S)-NH-;

[0034] L 2 Silver -O-, -C(=O)-, -CH(-OH)-, -CH2-CH(-NH2)-, , or and;

[0035] L 3 Silver -C(=O)-, -(CH2) n -, or -(CH2) n -O- and;

[0036] n is an integer from 1 to 6;

[0037] A is or and;

[0038] R 1 and R 2 are each independently H, halogen, -OH, haloC 1-6 Alkyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -CN, -COOH,C 1-6 Alkyl, Allyl, C 3-6 Cycloalkyl, amino, -NH-C(=O)-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkoxy, -C(=O)-C 1-6 Alkoxy, or am.

[0039] In the above chemical formula 1, the substitution position of the X group may be carbon 7, 8, 9, or 10 in 5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridine.

[0040] The various substitution positions of the X group can be exemplified by the chemical formulas 1-1 to 1-4 below.

[0041]

[0042] According to one embodiment, in the chemical formula 1, R is H, C 1-10 Alkyl or -L 1 -R 1 and; L 1 Silver -(CH2) n -, -C(=O)-, -C(=O)-O-, -S(=O)2- or -C(=S)-NH-; n is an integer from 1 to 6; R 1 Silver -OH or C 1-3 It's alkyl.

[0043] According to another embodiment, in the above chemical formula 1, R is -A, -L 1 -A, -L 1 -L 2 -A or -L 1 -L 2 -L 3 -A and L 1 Silver -(CH2) n - or -C(=O)-; L 2 Silver -O- or and;

[0044] L 3 is -C(=O)-; n is an integer from 1 to 6; A is and; R 1 and R 2 are each independently H, -Cl, or C 1-3 It's alkyl.

[0045] According to another embodiment, in the above chemical formula 1, R is -L 1 -R 1 , -L 1 -L 2 -A or -L1 -L 2 -L 3 -A and L 1 Silver -(CH2) n -and; L 2 is -CH(-OH)- or and; L 3 Silver -(CH2) n - and n is an integer from 1 to 6; A is or and; R 1 and R 2 are all H.

[0046] According to another embodiment, in the above chemical formula 1, R is -L 1 -L 2 -A or -L 1 -L 2 -L 3 -A and L 1 Silver -(CH2) n - or -C(=O)-; L 2 is -O-, -CH(-OH)- or and; L 3 Silver -C(=O)- or -(CH2) n -O- and; n is an integer from 1 to 6; A is and; R 1 and R 2 are each independently H or C 1-3 It's alkyl.

[0047] According to another embodiment, in the above chemical formula 1, R is -A, -L 1 -A, -L 1 -L 2 -A, or -L 1 -L 2 -L 3 -A and L 1 Silver -(CH2) n - or -C(=O); L 2 is -O-, -C(=O)-, -CH(-OH)-, -CH2-CH(-NH2)-, or and; L 3is -C(=O)-, or -(CH2) n - and n is an integer from 1 to 6; A is or and; R 1 and R 2 are each independently H, -F, -Cl, -Br, -OH, -CF3, -CN, -COOH, or C 1-3 It's alkyl.

[0048] According to another embodiment, in the above chemical formula 1, R is -L 1 -L 2 -A, or -L 1 -L 2 -L 3 -A and L 1 Silver -(CH2) n and; L 2 is -O- or -CH(-OH)-; L 3 Silver -(CH2) n -O- and A is or and; R 1 and R 2 are each independently H, F, C 1-6 Alkyl, C 1-6 Alkoxy, -CF3, allyl, -COOH, C 3-6 Cycloalkyl, amino, -C(=O)-C 1-6 Alkoxy, or am.

[0049] According to a specific implementation example, the tricyclic derivative may be represented by the following chemical formula 1a.

[0050] [Chemical Formula 1a]

[0051]

[0052] In the above formula

[0053] X is H, halogen, C 1-6 Alkyl, or C 1-6 It is alkoxy;

[0054] R 1 and R 2 are each independently H, halogen, -OH, C 1-6 Alkyl, haloC 1-6 Alkyl, or C 1-6 It is alkoxy.

[0055] According to another specific embodiment, the tricyclic derivative may be represented by the following chemical formula 1b.

[0056] [Chemical Formula 1b]

[0057]

[0058] In the above formula

[0059] X is H, halogen, C 1-6 Alkyl, or C 1-6 It is alkoxy;

[0060] R 1 and R 2 are each independently H, halogen, -OH, C 1-6 Alkyl, haloC 1-6 Alkyl, or C 1-6 It is alkoxy.

[0061] According to another specific embodiment, the tricyclic derivative may be represented by the following chemical formula 1c.

[0062] [Chemical Formula 1c]

[0063]

[0064] In the above formula

[0065] X is H, halogen, C 1-6 Alkyl, or C 1-6 It is alkoxy;

[0066] A is or and;

[0067] R 1 and R 2 are each independently H, halogen, -OH, C 1-6 Alkyl, haloC 1-6 Alkyl, or C 1-6 It is alkoxy.

[0068] The compound of the present invention includes a pharmaceutically acceptable salt of a tricyclic derivative represented by the above chemical formula 1.

[0069] The pharmaceutically acceptable salt should have low toxicity to humans and should not have any negative effects on the biological activity or physicochemical properties of the parent compound. For example, the pharmaceutically acceptable salt may be an acid addition salt formed with a pharmaceutically acceptable free acid.

[0070] The above-mentioned acid may be an inorganic acid or an organic acid. In this case, the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydrobromic acid, etc., and the organic acid may be acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, etc.

[0071] The above acid addition salt can be prepared by a conventional method, for example, by dissolving the compound of formula 1 in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent, for example, methanol, ethanol, acetone or acetonitrile.

[0072] In addition, the pharmaceutically acceptable salt may be an alkali metal salt (such as a sodium salt) or an alkaline earth metal salt (such as a potassium salt). The alkali metal salt or alkaline earth metal salt can be obtained, for example, by dissolving the compound of formula 1 in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and then evaporating and drying the filtrate.

[0073] Additionally, the compounds of the present invention may have a chiral carbon center and may therefore exist in the form of R or S isomers, racemates, individual enantiomers or mixtures, individual diastereomers or mixtures, and all such stereoisomers and mixtures thereof may fall within the scope of the present invention.

[0074] Additionally, the compounds of the present invention may include prodrugs of the compound of formula 1. The prodrug may refer to a functional derivative of the compound and is readily convertible into the compound in vivo. Prodrugs may be useful in some situations because they may be more easily administered than the compound in question. For example, unlike the compound in question, these prodrugs may be available to the body by oral administration. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the compound in question. Prodrugs may also be converted into the drug in question by various mechanisms, including enzymatic processes and metabolic hydrolysis. An example of a prodrug is a compound in which the amino group of the compound in question is protected with a protecting group such as t-butyloxycarbonyl (Boc).

[0075] Additionally, the compound of the present invention may include a hydrate or solvate of the compound of the above formula 1. The hydrate or solvate may be prepared using a known method, and is preferably non-toxic and water-soluble. In particular, the hydrate or solvate may preferably be one in which 1 to 5 molecules of water or an alcoholic solvent (particularly, ethanol, etc.) are bound.

[0076] As a specific example, specific examples of the compounds of the present invention are as follows:

[0077] 1) Ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate;

[0078] 2) 8-chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine dihydrochloride;

[0079] 3) 8-chloro-11-(1-(methylsulfonyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

[0080] 4) 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-isopropylpiperidine-1-carbothioamide;

[0081] 5) 1-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethan-1-one;

[0082] 6) (R)-3-amino-1-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one dihydrochloride;

[0083] 7) (S)-2-amino-3-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carbonyl)phenyl)propionic acid dihydrochloride;

[0084] 8) (S)-1-(2-amino-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-4-oxobutyl)-5,5-difluoropiperidin-2-one dihydrochloride;

[0085] 9) 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one;

[0086] 10) 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one;

[0087] 11) 2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-1-(6-methylimidazo[2,1-b]thiazol-5-yl)ethan-1-one;

[0088] 12) 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)quinazoline-2,4(1H,3H)-dione;

[0089] 13) 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

[0090] 14) (S)-2-amino-3-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propionic acid trihydrochloride;

[0091] 15) 2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-1-(6-methylimidazo[2,1-b]thiazol-5-yl)ethan-1-ol;

[0092] 16) Ethyl (S)-2-((t-butoxycarbonyl)amino)-3-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propanoate;

[0093] 17) (S)-2-((t-butoxycarbonyl)amino)-3-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propionic acid;

[0094] 18) 7-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one;

[0095] 19) 2-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butyl)hexahydro-1H-isoindole-1,3(2H)-dione;

[0096] 20) (S)-2-Amino-3-(3-chloro-4-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propionic acid trihydrochloride;

[0097] 21) (S)-2-Amino-3-(3-chloro-4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propionic acid trihydrochloride;

[0098] 22) (S)-2-Amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propionic acid trihydrochloride;

[0099] 23) (2S,4S)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)pyrrolidine-2-carboxylic acid trihydrochloride;

[0100] 24) 1-(4-bromophenyl)-2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethan-1-one;

[0101] 25) (4R,7S)-2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione;

[0102] 26) 2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-isoindole-1,3(2H)-dione;

[0103] 27) 1-(4-bromophenyl)-2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethan-1-ol;

[0104] 28) (2S,4R)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)pyrrolidine-2-carboxylic acid;

[0105] 29) (S)-2-Amino-3-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)phenyl)propionic acid dihydrochloride;

[0106] 30) (4R,7S)-2-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione;

[0107] 31) Ethyl (S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate trihydrochloride;

[0108] 32) 4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butan-1-ol;

[0109] 33) 3-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butyl)-1H-indole-5-carbonitrile;

[0110] 34) t-Butyl ((2S,3R)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-yl)carbamate;

[0111] 35) (2R,3S)-3-amino-1-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-4-phenylbutan-2-ol;

[0112] 36) Trans-methyl 2-(-4-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)cyclohexyl)acetate;

[0113] 37) 2-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropyl)hexahydro-1H-isoindole-1,3(2H)-dione;

[0114] 38) (4R,7S)-2-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione;

[0115] 39) 6-chloro-5-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)indolin-2-one;

[0116] 40) trans-methyl 2-(-4-(4-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)cyclohexyl)acetate;

[0117] 41) trans-2-(4-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)cyclohexyl)acetic acid;

[0118] 42) trans-2-(4-(4-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)cyclohexyl)acetic acid;

[0119] 43) (S)-2-((t-butoxycarbonyl)amino)-3-(4-(((2S,3R)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)phenyl)propionic acid;

[0120] 44) (S)-2-amino-3-(4-(((2S,3R)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)phenyl)propionic acid trihydrochloride;

[0121] 45) trans-2-(4-(4-(((2S,3R)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)phenyl)cyclohexyl)acetic acid;

[0122] 46) N-((2S,3R)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-yl)-2-phenyl-5-(trifluoromethyl)oxazole-4-carboxamide;

[0123] 47) (4R,7S)-2-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione;

[0124] 48) 8-Chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

[0125] 49) Isopropyl (S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate trihydrochloride;

[0126] 50) Neopentyl (S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate trihydrochloride;

[0127] 51) Cyclopentyl (S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate trihydrochloride;

[0128] 52) 4-((3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)oxy)-4-oxobutanoic acid;

[0129] 53) 2-((1R,4R)-4-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)cyclohexyl)acetic acid;

[0130] 54) 4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)-4''-(trifluoromethoxy)-[1,1':3',1''-terphenyl]-5'-carboxylic acid;

[0131] 55) (2S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)propionic acid trihydrochloride;

[0132] 56) 3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea;

[0133] 57) N-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)acetamide;

[0134] 58) t-Butyl (4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)carbamate;

[0135] 59) N-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)-2-(4-fluorophenyl)acetamide;

[0136] 60) 1-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-ol;

[0137] 61) 1-(2-allylphenoxy)-3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propan-2-ol;

[0138] 62) (E)-1-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-(2-(3-methoxystyryl)phenoxy)propan-2-ol;

[0139] 63) 9-Hydroxy-3-(2-(4-(8-methoxy-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one;

[0140] 64) 9-Hydroxy-2-methyl-3-(2-(4-(8-methyl-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one;

[0141] 65) 3-(2-(4-(5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one;

[0142] 66) (S)-2-Amino-3-(4-(4-(8-methoxy-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propionic acid trihydrochloride;

[0143] 67) (S)-2-Amino-3-(4-(4-(8-methyl-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propionic acid trihydrochloride;

[0144] 68) (S)-2-Amino-3-(4-(4-(5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propionic acid trihydrochloride;

[0145] 69) (4R,7S)-2-((trans-2-((4-(8-methoxy-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione;

[0146] 70) (4R,7S)-2-((trans-2-((4-(5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione;

[0147] 71) (4R,7S)-2-((trans-2-((4-(8-methyl-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione;

[0148] 72) 2-((trans-2-((4-(8-methoxy-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-isoindole-1,3(2H)-dione;

[0149] 73) 2-((trans-2-((4-(5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-isoindole-1,3(2H)-dione; and

[0150] 74) 2-((trans-2-((4-(8-methyl-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-isoindole-1,3(2H)-dione.

[0151] In another aspect, the present invention provides the use of a compound which is a tricyclic derivative represented by the above chemical formula 1, a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, as a serotonin antagonist (particularly a serotonin 2A antagonist).

[0152] In addition, the present invention provides a use of a compound which is a tricyclic derivative represented by the above chemical formula 1, a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, for the prevention or treatment of a disease associated with the activation of serotonin.

[0153] Here, “prevention” means any action that inhibits or delays the occurrence, spread, and recurrence of a metabolic disease or a hyperproliferative disease by administering the pharmaceutical composition, and “treatment” means any action that improves or beneficially changes the symptoms of the disease by administering the pharmaceutical composition.

[0154] The present invention also provides a use of a compound which is a tricyclic derivative represented by the above chemical formula 1, a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, for the manufacture of a medicament for preventing or treating a disease associated with the activation of serotonin. The present invention also provides a use of a compound which is a tricyclic derivative represented by the above chemical formula 1, a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, for the manufacture of a medicament for inhibiting the activity of serotonin.

[0155] In addition, the present invention provides a method for preventing or treating a disease associated with serotonin activation, comprising administering to a subject in need thereof a compound which is a tricyclic derivative represented by the above chemical formula 1, a pharmaceutically acceptable salt, a stereoisomer or a prodrug thereof. In addition, the present invention provides a method for inhibiting serotonin activity, comprising administering to a subject in need thereof a compound which is a tricyclic derivative represented by the above chemical formula 1, a pharmaceutically acceptable salt, a stereoisomer or a prodrug thereof. Here, the term "subject in need" refers to all animals including humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats and rabbits that have developed or may develop a disease associated with serotonin activation.

[0156] In addition, "administration" means providing a given substance to a subject in need thereof by any appropriate method, and the route of administration of the compound of the present invention can be administered through any general route as long as it can reach the target tissue.

[0157] In addition, the present invention, in another aspect, provides a pharmaceutical composition for inhibiting serotonin activity, comprising a compound which is a tricyclic derivative represented by the above chemical formula 1, a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, as an active ingredient.

[0158] In addition, the present invention, in another aspect, provides a pharmaceutical composition for preventing or treating a disease related to serotonin activation, comprising a compound which is a tricyclic derivative represented by the above chemical formula 1, a pharmaceutically acceptable salt, stereoisomer or prodrug thereof as an active ingredient.

[0159] The serotonin that the compound or pharmaceutical composition of the present invention is intended to inhibit is particularly serotonin 2A (5-HT 2A ) may be.

[0160] Additionally, the disease related to serotonin activation to be prevented or treated in the present invention may be a metabolic disease or cancer.

[0161] The metabolic disease may be any one selected from the group consisting of obesity, diabetes, hyperlipidemia, arteriosclerosis, fatty liver, steatohepatitis, fibrosis, and hypertension. Here, the fatty liver and steatohepatitis include alcoholic fatty liver disease, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

[0162] Additionally, the cancer may be any one selected from the group consisting of colon cancer, breast cancer, and ovarian cancer.

[0163] The pharmaceutical composition of the present invention may contain a compound that is a tricyclic derivative represented by the above chemical formula 1, a pharmaceutically acceptable salt, stereoisomer or prodrug thereof as an active ingredient, in an amount of 0.1 to 90 wt%, specifically 0.1 to 75 wt%, and more specifically 1 to 50 wt%, based on the total weight of the composition.

[0164] The composition of the present invention may further comprise, in addition to the compound of the present invention, conventional, non-toxic, pharmaceutically acceptable additives formulated into a formulation according to conventional methods as active ingredients. For example, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent, or excipient.

[0165] Examples of additives used in the composition of the present invention may include sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, and the like. For example, the additives may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavoring, and the like.

[0166] The composition of the present invention can be formulated in various formulations for oral administration (e.g., tablets, pills, powders, capsules, syrups or emulsions) or parenteral administration (e.g., intramuscular, intravenous or subcutaneous injection).

[0167] Preferably, the composition of the present invention can be formulated as a preparation for oral administration, and the additives used in this case can include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc.

[0168] Specifically, solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations can be formulated by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used.

[0169] In addition, liquid preparations for oral administration may include suspensions, solutions, emulsions, syrups, etc., and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.

[0170] Additionally, preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include withepsol, macrogol, Tween 61, cacao butter, laurin, and glycerogelatin. Meanwhile, injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0171] The compound or composition of the present invention may be administered to a patient in a therapeutically effective amount or a pharmaceutically effective amount.

[0172] Here, the term "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of a compound or composition that is effective in preventing or treating a target disease, and is sufficient to treat the disease at a reasonable benefit / risk ratio applicable to medical treatment, and does not cause side effects. The level of the effective amount may be determined based on factors including the patient's health condition, type and severity of the disease, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration and excretion rate, duration of treatment, drugs used in combination or concurrently, and other factors well known in the medical field.

[0173] The compound or composition of the present invention can be administered as an individual therapeutic agent or in combination with another therapeutic agent, sequentially or simultaneously with conventional therapeutic agents, or in single or multiple doses. Considering all of the above factors, it is important to administer an amount that achieves maximum effect with the minimum amount possible without causing side effects, and this can be readily determined by those skilled in the art.

[0174] Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the patient's age, sex, and weight, and is generally 0.1 to 1000 mg per kg of body weight, preferably 5 to 200 mg, administered daily or every other day, or divided into 1 to 3 times a day. However, since the amount may increase or decrease depending on the route of administration, severity of the disease, sex, body weight, age, etc., the scope of the present invention is not limited thereto.

[0175] Preferably, the compounds or compositions of the present invention may be administered for tumor therapy in combination with chemotherapy, radiation therapy, immunotherapy, hormonal therapy, bone marrow transplantation, stem cell replacement therapy, other biological therapies, surgical intervention, or a combination thereof. For example, the compounds or compositions of the present invention may be used as adjuvant therapy in conjunction with other long-term treatment strategies, or to maintain the patient's condition after tumor regression or chemoprevention in critically ill patients.

[0176] Preferably, the pharmaceutical composition of the present invention may further comprise one or more active ingredients, wherein the additional active ingredients are anti-proliferative compounds, such as aromatase inhibitors, anti-estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-activating compounds, alkylating compounds, histone deacetylase inhibitors, compounds inducing cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, anti-neoplastic anti-metabolites, platinum compounds, compounds targeting / reducing protein or lipid kinase activity, anti-angiogenic compounds, compounds targeting, reducing or inhibiting the activity of protein or lipid phosphatases, gonadorelin agonists, anti-androgens, methionine aminopeptidase inhibitors, bisphosphonates, biological response modifiers, anti-proliferative antibodies, heparanase inhibitors, inhibitors of Ras oncogenic isoforms. inhibitors, telomerase inhibitors, proteasome inhibitors, compounds used in the treatment of hematological malignancies, compounds targeting, decreasing or inhibiting the activity of Flt-3, Hsp90 inhibitors, kinesin spindle protein inhibitors, MEK inhibitors, leucovorin, EDG binding agents, anti-leukemic compounds, ribonucleotide reductase inhibitors, S-adenosylmethionine decarboxylase inhibitors, hemostatic steroids, corticosteroids, other chemotherapeutic compounds, photosensitizing compounds, but are not limited thereto.

[0177] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are provided merely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited by the examples.

[0178] Example 2: Preparation of 8-chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine dihydrochloride

[0179]

[0180] Loratadine (10 g, 26.117 mmol) was added to 100 mL of concentrated hydrochloric acid solution and refluxed with stirring for 12 hours. Afterwards, the excess hydrochloric acid solution was evaporated to obtain the title compound (9.5 g, yield 95%). 1 H NMR (300 MHz, DMSO-d6): δ 9.43 (bs, 3H), 8.67 (d, J = 5.49 Hz, 1H), 8.39 (d, J = 7.63 Hz, 1H), 7.93-7.81 (m, 1H), 7.47-7.39 (m, 1H), 7.34 (d, J = 8.24 Hz, 1H), 7.20 (d, J = 7.93 Hz, 1H), 3.20-2.30 (m, 12H).

[0181] Example 9: Preparation of 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

[0182]

[0183] Step 1: Preparation of 8-chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

[0184] Loratadine (2 g, 5.2 mmol) was dissolved in 10 mL of concentrated hydrochloric acid and refluxed for 12 hours. After evaporating the hydrochloric acid solution, water was added to the mixed solution. The pH was adjusted to 8 with ammonium hydroxide, and the mixed solution was extracted with dichloromethane and washed with water and brine. The recovered organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the title compound as a white solid (1.5 g, yield 92%). 1H NMR (400 MHz, DMSO-d6): δ 8.32 (d, J=4.58 Hz, 1H), 7.56 (d, J=7.63 Hz, 1H), 7.28 (s, 1H), 7.23-7.15 (m, 2H), 7.06 (dd, J=8.24, 1.53 Hz, 1H), 3.46-3.21 (m, 3H), 2.93-2.75 (m, 4H), 2.65-2.53 (m, 1H), 2.34-2.04 (m, 4H); LCMS [M+H] 311.1

[0185] Step 2: Preparation of 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

[0186] The compound obtained from Step 1 of Example 9 (120 mg, 0.313 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and then sodium carbonate (99.43 mg, 0.938 mmol), potassium iodide (51.91 mg, 0.313 mmol), and 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (77.74 mg, 0.344 mmol) were sequentially added, and the mixture was heated to 80°C. After completion of the reaction, the mixture was extracted twice with brine and ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (140 mg, yield 89%). 1 H NMR (300 MHz, MeOD): δ 8.49 (dd, J= 4.88, 1.22 Hz, 1H), 7.87 (d, J= 7.63 Hz, 1H), 7.50-7.44 (m, 1H), 7.38 (d, J= 2.14 Hz, 1H), 7.35-7.23 (m, 2H), 4.92-4.78 (m, 2H), 3.65-3.28 (m, 9H), 2.96-2.43 (m, 16H)

[0187] Example 10: Preparation of 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

[0188]

[0189] Step 1: Preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

[0190] In a 10 L reaction vessel equipped with a gas purger and a thermo pocket, 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride (400 g, 1.45 mol) was dissolved in methanol (4800 mL) and stirred. The reaction vessel was filled with nitrogen gas, and 10% Pd / C / RD-854 (80 g) was added. The resulting solution was heated to 55°C and stirred for 2 hours while slowly introducing hydrogen gas. After the reaction was completed, the mixed solution was cooled to room temperature and the Pd / C was removed by filtration through Celite under nitrogen gas. The residue was washed with methanol (2 x 400 mL) and concentrated. Water (1480 mL) was added to the obtained compound and heated to 80-85°C for 15 minutes. After the mixed solution was cooled to room temperature, potassium acetate (285.4 g, 2.9077 mol) dissolved in 300 mL of water was slowly added over 1 hour. The solution was stirred at room temperature for 1 hour, cooled to 8-12°C for 2 hours, and then stirred. The resulting crystals were filtered and washed with ethylenediaminetetraacetic acid disodium salt dihydrate (2 g) dissolved in 400 mL of water, and then washed with water (400 mL) and isopropyl alcohol (200 mL) to obtain a solid. The solid was dried under vacuum to obtain the title compound as a white solid (266 g, yield 75%). 1 H NMR (400 MHz, DMSO-d6): δ 5.71 (s, 1H), 4.48-4.41 (m, 1H), 3.96-3.84 (m, 1H), 3.78-3.62 (m, 3H), 2.95-2.85 (m, 2H), 2.28 (s, 3H), 2.06-1.74 (m, 4H); LCMS [M+H] 243.1

[0191] Step 2: Preparation of 8-chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

[0192] Loratadine (2 g, 5.2 mmol) was dissolved in 10 mL of concentrated hydrochloric acid and refluxed for 12 hours. After evaporating the hydrochloric acid solution, water was added to the mixed solution. The pH was adjusted to 8 with ammonium hydroxide, and the mixed solution was extracted with dichloromethane and washed with water and brine. The recovered organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the title compound as a white solid (1.5 g, yield 92%). 1 H NMR (400 MHz, DMSO-d6): δ 8.32 (d, J=4.58 Hz, 1H), 7.56 (d, J=7.63 Hz, 1H), 7.28 (s, 1H), 7.23-7.15 (m, 2H), 7.06 (dd, J=8.24, 1.53 Hz, 1H), 3.46-3.21 (m, 3H), 2.93-2.75 (m, 4H), 2.65-2.53 (m, 1H), 2.34-2.04 (m, 4H); LCMS [M+H] 311.1

[0193] Step 3: Preparation of 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

[0194] The compound obtained from step 2 of Example 10 (500 mg, 1.609 mmol) was dissolved in 4 mL of N,N-dimethylformamide, and then sodium carbonate (511.49 mg, 4.826 mmol), potassium iodide (267.04 mg, 1.0609 mmol), and the compound obtained from step 1 of Example 10 (390.41 mg, 1.609 mmol) were sequentially added, and the mixed solution was heated to 80°C. After completion of the reaction, the mixture was washed twice with ethyl acetate and brine. The recovered organic layer was filtered over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (745 mg, yield 90%).1 H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J= 4.58 Hz, 1H), 7.53 (d, J= 7.63 Hz, 1H), 7.26 (s, 1H), 7.21-7.12 (m, 2H), 7.04 (d, J= 7.93 Hz, 1H), 5.63 (d, J= 4.27 Hz, 1H), 4.43-4.34 (m, 1H), 3.89-3.78 (m, 1H), 3.67-3.55 (m, 1H), 3.29 (s, 3H), 3.35-3.20 (m, 2H), 2.86-2.42 (m, 6H), 2.40-2.04 (m, 10H), 1.98-1.68 (m, 2H); LCMS [M+H] 517.2

[0195] Example 22: Preparation of (S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propionic acid trihydrochloride

[0196]

[0197] Step 1: Preparation of ethyl (t-butoxycarbonyl)-L-tyrosine

[0198]

[0199] L-Tyrosine (100 g, 0.552 mol) was dissolved in 800 mL of ethanol, and thionyl chloride (100.1 mL, 1.38 mol) was slowly added while stirring. The mixed solution was stirred at 0°C for 1 hour and then refluxed overnight. After completion of the reaction, the mixed solution was concentrated to remove volatile substances to obtain ethyl L-tyrosinate hydrochloride. Ethyl L-tyrosinate hydrochloride was added to 100 mL of methanol and 800 mL of dichloromethane, and the mixture was stirred at room temperature. Then, triethylamine (154 mL, 1.1 mol) and di-t-butyl dicarbonate (120.5 g, 0.552 mol) dissolved in 200 mL of dichloromethane were sequentially added to the reaction solution at 0°C. The mixed solution was stirred at room temperature overnight, and the solid was removed by filtration. Water was added to the mixed solution to extract, the organic layer was treated with sodium sulfate, and then concentrated to obtain the title compound (136 g, yield 80%) as a white solid.

[0200] Step 2: Preparation of ethyl (S)-3-(4-(3-bromopropoxy)phenyl)-2-((t-butoxycarbonyl)amino)propanoate

[0201]

[0202] Ethyl (t-butoxycarbonyl)-L-tyrosinate (2 g, 6.645 mmol), calcium carbonate (902.39 mg, 6.53 mmol), and 1,3-dibromopropane (3.92 g, 19.39 mmol) were dissolved in 20 mL of N,N-dimethylformamide, and the mixture was stirred at 100°C for 7 hours. After cooling the mixture to room temperature, 200 mL of water was added, the mixture was extracted with ethyl acetate, and washed with brine. The organic layer was treated with sodium sulfate, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound (1.1 g, yield 40%).

[0203] Step 3: Preparation of ethyl (S)-2-((t-butoxycarbonyl)amino)-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate

[0204]

[0205] 8-Chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (200 mg, 0.521 mmol) was dissolved in 4 mL of N,N-dimethylformamide and stirred. Sodium carbonate (209.91 mg, 1.98 mmol) and ethyl (S)-3-(4-(3-bromopropoxy)phenyl)-2-((t-butoxycarbonyl)amino)propanoate (246.69 mg, 0.573 mmol) were sequentially added to the reaction solution. The mixed solution was then heated to 80°C and stirred for 3 hours. After completion of the reaction, the mixed solution was extracted by adding brine and ethyl acetate. The organic layer was treated with sodium sulfate, the filtrate was concentrated, and the resulting mixture was purified by silica gel column chromatography to obtain the title compound (310 mg, yield 90%).

[0206] Step 4: Preparation of (S)-2-((t-butoxycarbonyl)amino)-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propionic acid

[0207]

[0208] The compound obtained in step 3 of Example 22 (310 mg, 0.469 mmol) was dissolved in 80 mL of tetrahydrofuran / water (3:1) solution, and sodium hydroxide (93.9 mg, 2.34 mmol) was added. The mixed solution was then stirred at room temperature for 24 hours. After completion of the reaction, tetrahydrofuran was evaporated and the pH was adjusted to 4 using 1 N hydrochloric acid solution. 50 mL of water was added and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated. The concentrated mixture was purified by silica gel column chromatography to obtain the title compound (260 mg, yield 87%).

[0209] Step 5: Preparation of (S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propionic acid trihydrochloride

[0210]

[0211] ((S)-2-((t-butoxycarbonyl)amino)-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propionic acid was dissolved in 10 mL of ethyl acetate, and then 10 mL of a 4.0 M hydrochloric acid solution of 1,4-dioxin was added. The mixed solution was then stirred for 12 hours. The mixed solution was concentrated and filtered to obtain the title compound (180 mg, yield 77%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.40 (s, 1H), 8.63-8.55 (m, 1H), 8.45 (bs, 3H), 8.24-8.11 (m, 1H), 7.79-7.63 (m, 1H), 7.42 (dd, J= 9.00, 2.14 Hz, 1H), 7.32 (d, J= 8.24 Hz, 1H), 7.29-7.11 (m, 3H), 6.90 (dd, J= 18.92, 8.54 Hz, 2H), 4.12-3.98 (m, 3H), 3.53-3.41 (m, 2H), 3.36-2.76 (m, 8H), 2.67-2.35 (m, 6H), 2.31-2.11 (m, 2H).

[0212] Example 25: Preparation of (4R,7S)-2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione

[0213]

[0214] Step 1: Preparation of ((1R,2R)-cyclohexane-1,2-diyl)bis(methylene) dimethanesulfonate

[0215]

[0216] Methanesulfonyl chloride (1.2 mL, 15.257 mmol) and triethylamine (2.5 mL, 17.337 mmol) were sequentially added to ((1R,2R)-cyclohexane-1,2-diyl)dimethanol (1 g, 6.935 mmol) dissolved in 50 mL of dichloromethane at 0-5°C. The temperature was gradually raised to room temperature, and the reaction solution was stirred for 2 hours. 50 mL of dichloromethane was added to the obtained mixture, and extraction was performed with water. The recovered organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (1.8 g, yield 86%).

[0217] Step 2: Preparation of ((1R,2R)-2-(((4R,7S)-1,3-dioxooctahydro-2H-4,7-methanolisoindol-2-yl)methyl)cyclohexyl)methyl methanesulfonate

[0218]

[0219] The compound (545 mg, 1.816 mmol) obtained from step 1 of Example 25, (4R,7S)-hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione (300 mg, 1.816 mmol) was dissolved in 20 mL of acetone, potassium carbonate (376.45 mg, 2.724 mmol) was added, and the mixture was refluxed for 12 hours. The obtained mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound (520 mg, yield 78%).

[0220] Step 3: Preparation of (4R,7S)-2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione

[0221]

[0222] The compound obtained from step 2 of Example 10 (200 mg, 0.521 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and then sodium carbonate (165.72 mg, 1.564 mmol) and the compound obtained from step 2 of Example 25 (211.84 mg, 0.573 mmol) were sequentially added, and the mixture was stirred at 80°C for 3 hours. After completion of the reaction, the mixture was extracted twice with brine and ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (250 mg, yield 82%). 1H NMR (300 MHz, CDCl3): δ 8.47-8.32 (m, 1H), 7.42 (d, J= 7.93 Hz, 1H), 7.24-7.02 (m, 4H), 4.01-3.11 (m, 4H), 2.93-0.93 (m, 32H)

[0223] Example 26: Preparation of 2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-isoindole-1,3(2H)-dione

[0224]

[0225] Step 1: Preparation of ((1R,2R)-2-((1,3-dioxooctahydro-2H-isoindol-2-yl)methyl)cyclohexyl)methyl methanesulfonate

[0226]

[0227] The compound (588.25 mg, 1.958 mmol) obtained from step 1 of Example 25, hexahydro-1H-isoindole-1,3(2H)-dione (300 mg, 1.958 mmol) was dissolved in 20 mL of acetone, potassium carbonate (405.94 mg, 2.937 mmol) was added, and the mixture was refluxed for 12 hours. The obtained mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound (550 mg, yield 79%).

[0228] Step 2: Preparation of 2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-isoindole-1,3(2H)-dione

[0229]

[0230] The compound obtained in step 2 of Example 10 (200 mg, 0.521 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and then sodium carbonate (165.72 mg, 1.564 mmol) and the compound obtained in step 1 of Example 26 (204.96 mg, 0.573 mmol) were sequentially added, and the mixture was heated at 80°C for 3 hours. After completion of the reaction, the mixture was extracted twice with brine and ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (260 mg, 87%). 1 H NMR (300 MHz, CDCl3): δ 8.44-8.34 (m, 1H), 7.41 (d, J= 7.93 Hz, 1H), 7.23-7.03 (m, 4H), 3.48-3.12 (m, 2H), 2.92-0.94 (m, 34H).

[0231] Example 31: Preparation of ethyl (S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate trihydrochloride

[0232]

[0233] The compound (900 mg, 1.36 mmol) obtained in step 3 of Example 22 was dissolved in 20 mL of ethyl acetate, 15 mL of a 4.0 M hydrochloric acid solution of 1,4-dioxin was added, and the mixture was stirred for 12 hours. Thereafter, the mixed solution was concentrated and filtered to obtain the title compound (810 mg, yield 88%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.66-8.47 (m, 4H), 8.24-8.08 (m, 1H), 7.78-7.60 (m, 1H), 7.39 (d, J= 11.29 Hz, 1H), 7.29 (d, J= 8.24 Hz, 1H), 7.17-7.07 (m, 3H), 6.93-6.79 (m, 2H), 4.21-3.94 (m, 5H), 3.49-3.37 (m, 2H), 3.30-2.08 (m, 18H), 1.13 (t, J= 7.02 Hz, 3H).

[0234] Example 48: Preparation of 8-chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

[0235]

[0236] The compound (5 g) obtained in Example 2 was dissolved in water, and then the pH was adjusted to 8 by adding aqueous ammonia solution. The mixed solution was then extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated to obtain the title compound. LC-MS (m / z): 311.1270 (M+H)

[0237] Example 51: Preparation of cyclopentyl (S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate trihydrochloride

[0238]

[0239] Step 1: Preparation of cyclopentyl (S)-3-(4-(3-bromopropoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate

[0240]

[0241] To cyclopentyl (tert-butoxycarbonyl)-L-tyrosinate (500 mg, 1.431 mmol) dissolved in 100 mL of tetrohydrofuran were added triphenylphosphine (563 g, 2.146 mmol) and 3-bromopropan-1-ol (298 mg, 2.146 mmol). The mixture was cooled to 0°C, and diisopropyl azodicarboxylate (DIAD, 0.4 mL, 2.146 mmol) was slowly added. The mixture was slowly warmed to room temperature and stirred for 24 hours. The obtained mixture was evaporated, extracted with water and ethyl acetate, and the recovered organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (560 mg, yield 83%).

[0242] Step 2: Preparation of cyclopentyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate

[0243]

[0244] The compound obtained from step 2 of Example 10 (170 mg, 0.443 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and then sodium carbonate (141 mg, 1.329 mmol) and the compound obtained from step 1 of Example 51 (219 mg, 0.465 mmol) were sequentially added, and the mixture was heated at 80°C for 3 hours. After completion of the reaction, the mixture was extracted twice with brine and ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (270 mg, 87%).

[0245] Step 3: Preparation of cyclopentyl (S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate trihydrochloride

[0246]

[0247] The compound (270 mg, 0.386 mmol) obtained from step 2 of Example 51 was dissolved in ethyl acetate (20 mL), and a 4 M hydrochloric acid solution of 1,4-dioxin was added and stirred. The mixed solution was evaporated and filtered to obtain the title compound (220 mg, yield 80%). 1 H NMR (300 MHz, DMSO-d6): δ 8.66 - 8.52 (m, 4H), 8.22 (s, 1H), 7.76 (s, 1H), 7.43 (dd, J = 11.14, 2.14 Hz, 1H), 7.33 (dd, J = 8.24, 2.14 Hz, 1H), 7.29 - 7.09 (m, 3H), 6.90 (dd, J = 18.62 , 8.54 Hz, 2H), 5.11 - 5.0 (m, 1H), 4.18 - 3.95 (m, 3H), 3.54 - 3.37 (m, 2H), 3.33 - 2.71 (m, 8H), 2.68 - 2.32 (m, 6H), 2.31 - 2.08 (m, 2H), 1.83 - 1.65 (m, 2H), 1.63 - 1.31 (m, 6H)

[0248] Example 63: Preparation of 9-hydroxy-3-(2-(4-(8-methoxy-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

[0249]

[0250] Step 1: Preparation of 8-methoxy-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

[0251] Ethyl 4-(8-methoxy-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate (150 mg, 0.396 mmol) was dissolved in 1 mL of concentrated hydrochloric acid solution and refluxed for 12 hours. The hydrochloric acid solution was evaporated and water was added. The pH was adjusted to 8 with ammonium hydroxide and extracted with dichloromethane. The recovered organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (110 mg, yield 90%).

[0252] Step 2: Preparation of 9-hydroxy-3-(2-(4-(8-methoxy-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

[0253] The compound obtained from step 1 of Example 63 (100 mg, 0.326 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and then sodium carbonate (103.77 mg, 0.979 mmol), potassium iodide (54.18 mg, 0.326 mmol), and the compound obtained from step 1 of Example 10 (79.21 mg, 0.326 mmol) were sequentially added and heated to 80°C. After completion of the reaction, the mixture was extracted twice with brine and ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (140 mg, 84%). LCMS [M+H] 513.2

[0254] The example compounds shown in Table 1 below were synthesized by the above synthetic route and similar routes.

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278] Experimental example: Measurement of inhibitory activity against serotonin 2A

[0279] For the compounds synthesized in the above examples, serotonin 2A (5-HT 2A ) was measured for inhibitory activity (in vitro), and the results are shown in Table 2 below.

[0280]

[0281] As shown in Table 2 above, the inhibitory activity of the compounds of the examples against serotonin 2A was confirmed. Therefore, the compounds according to the present invention can be usefully used in the prevention or treatment of diseases related to serotonin activation, such as metabolic diseases such as obesity and fatty liver (salt).

Claims

1. A compound which is a tricyclic derivative represented by the following chemical formula 1, a pharmaceutically acceptable salt, stereoisomer or prodrug thereof: [Chemical Formula 1] In the above formula X is H, halogen, C 1-6 Alkyl, or C 1-6 It is alkoxy; R is H, C 1-10 Alkyl, -A, -L 1 -R 1 , -L 1 -A, -L 1 -L 2 -A, or -L 1 -L 2 -L 3 -A and; L 1 Silver -(CH2) n -, -C(=O)-, -C(=O)-O-, -CH(-OH)-CH2-, -S(=O)2-, or -C(=S)-NH-; L 2 Silver -O-, -C(=O)-, -CH(-OH)-, -CH2-CH(-NH2)-, , or and; L 3 Silver -C(=O)-, -(CH2) n -, or -(CH2) n -O- and; n is an integer from 1 to 6; A is or and; R 1 and R 2 are each independently H, halogen, -OH, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC1-6 Alkoxy, -CN, -COOH,C 1-6 Alkyl, Allyl, C 3-6 Cycloalkyl, amino, -NH-C(=O)-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkoxy, -C(=O)-C 1-6 Alkoxy, or am.

2. In paragraph 1, R is H, C 1-10 Alkyl or -L 1 -R 1 and; L 1 Silver -(CH2) n -, -C(=O)-, -C(=O)-O-, -S(=O)2- or -C(=S)-NH-; n is an integer from 1 to 6; R 1 Silver -OH or C 1-3 Alkyl, compound.

3. In paragraph 1, R is -A, -L 1 -A, -L 1 -L 2 -A or -L 1 -L 2 -L 3 -A and; L 1 Silver -(CH2) n - or -C(=O)-; L 2 Silver -O- or and; L 3 is -C(=O)-; n is an integer from 1 to 6; A is and; R 1 and R 2 are each independently H, -Cl, or C 1-3 Alkyl, compound.

4. In paragraph 1, R is -L1 -R 1 , -L 1 -L 2 -A or -L 1 -L 2 -L 3 -A and; L 1 Silver -(CH2) n - and; L 2 is -CH(-OH)- or and; L 3 Silver -(CH2) n - and; n is an integer from 1 to 6; A is or and; R 1 and R 2 are all H compounds.

5. In paragraph 1, R is -L 1 -L 2 -A or -L 1 -L 2 -L 3 -A and; L 1 Silver -(CH2) n - or -C(=O)-; L 2 is -O-, -CH(-OH)- or and; L 3 Silver -C(=O)- or -(CH2) n -O- and; n is an integer from 1 to 6; A is and; R 1 and R 2 are each independently H or C 1-3 Alkyl, compound.

6. In paragraph 1, R is -A, -L 1-A, -L 1 -L 2 -A, or -L 1 -L 2 -L 3 -A and; L 1 Silver -(CH2) n - or -C(=O); L 2 is -O-, -C(=O)-, -CH(-OH)-, -CH2-CH(-NH2)-, or and; L 3 Silver -C(=O)-, or -(CH2) n - and; n is an integer from 1 to 6; A is or and; R 1 and R 2 are each independently H, -F, -Cl, -Br, -OH, -CF3, -CN, -COOH, or C 1-3 Alkyl, compound.

7. In paragraph 1, R is -L 1 -L 2 -A, or -L 1 -L 2 -L 3 -A and; L 1 Silver -(CH2) n and; L 2 is -O- or -CH(-OH)-; L 3 Silver -(CH2) n -O- and; A is or and; R 1 and R 2 are each independently H, F, C 1-6 Alkyl, C 1-6 Alkoxy, -CF3, Allyl, -COOH, C 3-6 Cycloalkyl, amino, -C(=O)-C 1-6 Alkoxy, or Person, compound.

8. In paragraph 1, The above tricyclic derivative is a compound represented by the following chemical formula 1a: [Chemical formula 1a] In the above formula X is H, halogen, C 1-6 Alkyl, or C 1-6 It is alkoxy; R 1 and R 2 are each independently H, halogen, -OH, C 1-6 Alkyl, HaloC 1-6 Alkyl, or C 1-6 It's alkoxy.

9. In paragraph 1, The above tricyclic derivative is a compound represented by the following chemical formula 1b: [Chemical formula 1b] In the above formula X is H, halogen, C 1-6 Alkyl, or C 1-6 It is alkoxy; R 1 and R 2 are each independently H, halogen, -OH, C 1-6 Alkyl, HaloC 1-6 Alkyl, or C 1-6 It's alkoxy.

10. In paragraph 1, The above tricyclic derivative is a compound represented by the following chemical formula 1c: [Chemical formula 1c] In the above formula X is H, halogen, C 1-6 Alkyl, or C 1-6 It is alkoxy; A is or and; R 1 and R 2 are each independently H, halogen, -OH, C 1-6 Alkyl, HaloC 1-6 Alkyl, or C 1-6 It's alkoxy.

11. In paragraph 1, The above compound is one compound selected from the group below: 1) Ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate; 2) 8-chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine dihydrochloride; 3) 8-chloro-11-(1-(methylsulfonyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine; 4) 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-isopropylpiperidine-1-carbothioamide; 5) 1-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethan-1-one; 6) (R)-3-Amino-1-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one dihydrochloride; 7) (S)-2-Amino-3-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carbonyl)phenyl)propionic acid dihydrochloride; 8) (S)-1-(2-amino-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-4-oxobutyl)-5,5-difluoropiperidin-2-one dihydrochloride; 9) 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one; 10) 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one; 11) 2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-1-(6-methylimidazo[2,1-b]thiazol-5-yl)ethan-1-one; 12) 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)quinazoline-2,4(1H,3H)-dione; 13) 8-Chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine; 14) (S)-2-Amino-3-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propionic acid trihydrochloride; 15) 2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-1-(6-methylimidazo[2,1-b]thiazol-5-yl)ethan-1-ol; 16) Ethyl (S)-2-((t-butoxycarbonyl)amino)-3-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propanoate; 17) (S)-2-((t-Butoxycarbonyl)amino)-3-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propionic acid; 18) 7-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one; 19) 2-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butyl)hexahydro-1H-isoindole-1,3(2H)-dione; 20) (S)-2-Amino-3-(3-chloro-4-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propionic acid trihydrochloride; 21) (S)-2-Amino-3-(3-chloro-4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propionic acid trihydrochloride; 22) (S)-2-Amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propionic acid trihydrochloride; 23) (2S,4S)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)pyrrolidine-2-carboxylic acid trihydrochloride; 24) 1-(4-bromophenyl)-2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethan-1-one; 25) (4R,7S)-2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione; 26) 2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-isoindole-1,3(2H)-dione; 27) 1-(4-bromophenyl)-2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethan-1-ol; 28) (2S,4R)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)pyrrolidine-2-carboxylic acid; 29) (S)-2-Amino-3-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)phenyl)propionic acid dihydrochloride; 30) (4R,7S)-2-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione; 31) Ethyl (S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate trihydrochloride; 32) 4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butan-1-ol; 33) 3-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butyl)-1H-indole-5-carbonitrile; 34) t-Butyl ((2S,3R)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-yl)carbamate; 35) (2R,3S)-3-Amino-1-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-4-phenylbutan-2-ol; 36) trans-methyl 2-(-4-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)cyclohexyl)acetate; 37) 2-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropyl)hexahydro-1H-isoindole-1,3(2H)-dione; 38) (4R,7S)-2-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione; 39) 6-chloro-5-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)indolin-2-one; 40) trans-methyl 2-(-4-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)cyclohexyl)acetate; 41) trans-2-(4-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)cyclohexyl)acetic acid; 42) trans-2-(4-(4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)cyclohexyl)acetic acid; 43) (S)-2-((t-butoxycarbonyl)amino)-3-(4-(((2S,3R)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)phenyl)propionic acid; 44) (S)-2-Amino-3-(4-(((2S,3R)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)phenyl)propionic acid trihydrochloride; 45) trans-2-(4-(4-(((2S,3R)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)phenyl)cyclohexyl)acetic acid; 46) N-((2S,3R)-4-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-yl)-2-phenyl-5-(trifluoromethyl)oxazole-4-carboxamide; 47) (4R,7S)-2-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione; 48) 8-Chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine; 49) Isopropyl (S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate trihydrochloride; 50) Neopentyl (S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate trihydrochloride; 51) Cyclopentyl (S)-2-amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate trihydrochloride; 52) 4-((3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)oxy)-4-oxobutanoic acid; 53) 2-((1R,4R)-4-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)cyclohexyl)acetic acid; 54) 4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)-4''-(trifluoromethoxy)-[1,1':3',1''-terphenyl]-5'-carboxylic acid; 55) (2S)-2-Amino-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)propionic acid trihydrochloride; 56) 3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea; 57) N-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)acetamide; 58) t-Butyl (4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)carbamate; 59) N-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-hydroxypropoxy)phenyl)-2-(4-fluorophenyl)acetamide; 60) 1-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-ol; 61) 1-(2-allylphenoxy)-3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propan-2-ol; 62) (E)-1-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-3-(2-(3-methoxystyryl)phenoxy)propan-2-ol; 63) 9-Hydroxy-3-(2-(4-(8-methoxy-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one; 64) 9-Hydroxy-2-methyl-3-(2-(4-(8-methyl-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one; 65) 3-(2-(4-(5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one; 66) (S)-2-Amino-3-(4-(4-(8-methoxy-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propionic acid trihydrochloride; 67) (S)-2-Amino-3-(4-(4-(8-methyl-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propionic acid trihydrochloride; 68) (S)-2-Amino-3-(4-(4-(5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)butoxy)phenyl)propionic acid trihydrochloride; 69) (4R,7S)-2-((trans-2-((4-(8-methoxy-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione; 70) (4R,7S)-2-((trans-2-((4-(5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione; 71) (4R,7S)-2-((trans-2-((4-(8-methyl-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione; 72) 2-((trans-2-((4-(8-methoxy-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-isoindole-1,3(2H)-dione; 73) 2-((trans-2-((4-(5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-isoindole-1,3(2H)-dione; and 74) 2-((trans-2-((4-(8-methyl-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-isoindole-1,3(2H)-dione.

12. A pharmaceutical composition for preventing or treating a disease related to serotonin activation, comprising a compound of any one of claims 1 to 11 as an active ingredient.

13. In paragraph 12, A pharmaceutical composition, wherein the disease associated with the above serotonin activation is a metabolic disease or cancer.

14. In paragraph 13, The above metabolic disease is any one selected from the group consisting of obesity, diabetes, hyperlipidemia, arteriosclerosis, fatty liver, steatohepatitis, fibrosis, and hypertension. A pharmaceutical composition, wherein the cancer is any one selected from the group consisting of colon cancer, breast cancer, and ovarian cancer.

15. Use of a compound according to any one of claims 1 to 11 for the prevention or treatment of a disease associated with serotonin activation.

16. Use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the prevention or treatment of a disease associated with serotonin activation.

17. Use of a compound according to any one of claims 1 to 11 as a serotonin antagonist.

18. Use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for inhibiting serotonin activity.

19. A method for preventing or treating a disease associated with serotonin activation, comprising administering to a subject in need thereof a compound of any one of claims 1 to 11.

20. A method for inhibiting serotonin activity, comprising administering to a subject in need thereof a compound of any one of claims 1 to 11.