Tricyclic derivative and pharmaceutical composition comprising same

Abstract

A tricyclic derivative represented by chemical formula (I), of the present invention, has a reversible proton pump inhibitory effect, and thus the tricyclic derivative and a pharmaceutical composition comprising same can be effectively used as a therapeutic agent for diseases associated with gastric acid secretion, particularly, as P-CAB.

Description

Tricyclic derivatives and pharmaceutical compositions containing the same

[0001] The present invention relates to a tricyclic derivative and a pharmaceutical composition comprising the same. Specifically, the present invention relates to a tricyclic derivative that can be used as a potassium-competitive acid blocker (P-CAB) and a pharmaceutical composition comprising the same.

[0002] Gastric acid plays a number of beneficial roles, including digesting proteins, absorbing minerals like calcium and iron, and sterilizing harmful microorganisms in ingested food. However, because gastric acid is extremely acidic, with a pH of 1-2, excessive gastric acid secretion or reflux into the esophagus can lead to digestive diseases such as peptic ulcers, gastric and duodenal ulcers, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD).

[0003] Gastrointestinal ulcers, gastritis, and reflux esophagitis occur when the balance between aggressive factors (e.g., gastric acid, Helicobacter pylori, pepsin, stress, alcohol, and tobacco) and defensive factors (e.g., gastric mucosa, bicarbonate, prostaglandins, blood supply, etc.) is disrupted. Therefore, treatments for gastrointestinal damage are divided into those that suppress aggressive factors or enhance defensive factors.

[0004] Representative related treatments include drugs that reduce aggressive factors, such as antacids, anticholinergic drugs, H2 receptor antagonists, and proton pump inhibitors (PPIs). Currently, proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, pantoprazole, and rabeprazole, are leading the market. However, it has been raised that existing PPIs can cause side effects such as bacterial proliferation in the stomach, promotion of proton pump expression, and possibility of tumor cell formation due to hypergastrinemia [Havu N, Digestion, 1986, 35(Suppl 1), 42-55; Chang Seok Song, Dong Il Park, Korean J Med., 2011, 81(1), 6~10], recently, it has also been reported that long-term use increases the risk of hip, wrist, and spine fractures by suppressing calcium absorption and bone cell growth through gastric acid suppression [Yang YX, et al., JAMA, 2006, 296, 2947~53; ​​Targownik LE, et al., CMAJ, 2008, 179(4), 319~26; Gray SL, et al., Arch Intern Med. 2010, 170(9), 765~71]. Furthermore, despite the highly effective therapeutic ability of proton pump inhibitors (PPIs), the number of patients refractory to PPIs is also rapidly increasing.

[0005] Meanwhile, drugs that enhance defense factors are also used to treat gastrointestinal ulcers and gastritis. Known drugs that enhance defense factors include mucoprotectors that bind to ulcer sites to form a physicochemical barrier, and drugs that promote mucus synthesis and secretion.

[0006] Meanwhile, Helicobacter pylori is a bacterium that exists in the stomach and is known to cause chronic gastritis, gastric ulcers, and duodenal ulcers, and many patients with gastrointestinal damage are infected with H. pylori. These patients must take antibiotics such as clarithromycin, amoxicillin, metronidazole, and tetracycline along with antiulcer drugs such as proton pump inhibitors and gastric acid pump antagonists, and various side effects have been reported.

[0007] Therefore, there is a need in the art for the development of anti-ulcer drugs that simultaneously suppress gastric acid secretion (e.g., proton pump inhibitory activity), enhance defense factors (e.g., increase mucus secretion), and eradicate Helicobacter pylori (H. pylori).

[0008] Accordingly, H + / K + -K of ATPase + There is growing interest in and demand for potassium-competitive acid blockers (P-CABs), drugs that reversibly bind to the binding site and suppress acid secretion through potassium-competitive inhibition. In particular, unlike irreversible proton pump inhibitors (PPIs), P-CABs exhibit rapid onset of action and are easy to take, regardless of mealtime. They are also expected to be highly effective in alleviating nocturnal symptoms, a problem with irreversible PPIs.

[0009] [Prior Art Literature]

[0010] [Non-patent literature]

[0011] (Non-patent literature 1) Havu N, Digestion, 1986, 35(Suppl 1), 42-55; Chang Seok Song, Dong Il Park, Korean J Med., 2011, 81(1), 6-10

[0012] (Non-patent literature 2) Yang YX, et al., JAMA, 2006, 296, 2947~53; ​​Targownik LE, et al., CMAJ, 2008, 179(4), 319~26; Gray SL, et al., Arch Intern Med. 2010, 170(9), 765~71

[0013] Accordingly, as a result of the research efforts of the present inventors, they confirmed that a tricyclic derivative represented by the chemical formula (I) described below can be used as a reversible proton pump inhibitor useful for the prevention or treatment of gastric acid secretion-related diseases, thereby completing the present invention.

[0014] Accordingly, the object of the present invention is to provide a novel tricyclic derivative, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0015] Another object of the present invention is to provide a pharmaceutical use of the tricyclic derivative, and specifically, to provide a pharmaceutical composition for treating or preventing a gastric acid secretion-related disease, which comprises the tricyclic derivative as an active ingredient.

[0016] Another object of the present invention is to provide a use for treating or preventing a gastric acid secretion-related disease using the tricyclic derivative, or a method for treating or preventing a gastric acid secretion-related disease comprising a step of administering the compound.

[0017] According to the above task, the present invention provides a compound represented by the following chemical formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0018] (I)

[0019] X here 1 , X 2 , Y, L, A, B, R 1 , R 2 , Z 1 , Z 2 , and Z 3 is as defined in the description of the invention.

[0020] The present invention also provides the use of a compound represented by the above chemical formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, as a potassium competitive acid blocker (P-CAB) or acid pump antagonist.

[0021] In addition, the present invention provides a pharmaceutical composition for preventing or treating a disease related to gastric acid secretion, comprising a compound represented by the above chemical formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof as an active ingredient.

[0022] The present invention provides a use for treating or preventing a gastric acid secretion-related disease using the compound, and a method for treating or preventing a gastric acid secretion-related disease comprising a step of administering the compound.

[0023] The compound represented by the chemical formula (I) according to the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, is capable of inhibiting H present in activated gastric parietal cells. + / K + K of ATPase + H competitively binds to the binding site +It has the effect of reducing gastric acid secretion by interfering with the exchange process. Accordingly, the compound of the present invention can be used as a potassium-competitive acid blocker (P-CAB) or acid pump antagonist, and a pharmaceutical composition containing it can be useful for the prevention or treatment of diseases related to gastric acid secretion.

[0024] The present invention will be described in more detail below.

[0025] Embodiments of the present invention may be modified in various forms, and the scope of the present invention is not limited to the embodiments described below. Furthermore, these embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art. Furthermore, throughout the specification, the term "comprising" a certain element does not exclude other elements, but rather implies the inclusion of other elements, unless specifically stated otherwise.

[0026] As used herein, the term “halo” or “halogen” means fluoro (F), chloro (Cl), bromo (Br), or iodo (I), unless otherwise stated.

[0027] The term "alkyl", unless otherwise specified, means a linear or branched saturated hydrocarbon moiety. For example, "C 1-10 "Alkyl" means an alkyl group having a skeleton of 1 to 10 carbons. Specifically, C 1-10Alkyl may include methyl, ethyl, normal-propyl, iso-propyl, normal-butyl, iso-butyl, secondary-butyl, tertiary-butyl, normal-pentyl, iso-pentyl, tertiary-pentyl, secondary-pentyl, neo-pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like.

[0028] The term "oxy" means -O-, for example C 1-3 Alkyleneoxy is C 1-3 It can mean alkylene-O-.

[0029] The term "alkoxy" means an alkyl group linked by -O-, for example C 1-4 Alkoxy may include, but is not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, and tert-butoxy.

[0030] The term "alkylamino" refers to an amino substituted with an alkyl. For example, C 1-6 Alkylamino is C 1-6 The alkyl group is amino, i.e., -NH(C 1-6 alkyl) and may include, but is not limited to, methylamino, ethylamino, propylamino, butylamino, pentylamino, and hexylamino.

[0031] The term "haloalkyl" means a straight or branched chain alkyl having carbon atoms substituted with one or more halo groups (F, Cl, Br, I). Examples of such haloalkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, and n-butyl substituted with one or more halo groups.

[0032] The term "cycloalkyl" refers to a non-aromatic hydrocarbon ring residue, which may include a single ring or multiple rings. The cycloalkyl may include a saturated ring, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Furthermore, the cycloalkyl may include an unsaturated ring having one or more carbon-carbon double bonds in the ring, as long as the ring does not have aromaticity due to the presence of the double bond, and for example, cyclopentenyl may also be included in the category. Depending on the number of carbons constituting the ring, C 3-15 Cycloalkyl, C 3-12 Cycloalkyl, C 3-10 Cycloalkyl, C 3-6 Cycloalkyl, C 6-12 Cycloalkyl, etc. are possible, but are not limited to these.

[0033] The term "aryl" refers to an aromatic hydrocarbon ring moiety, which may include a single ring or multiple rings, and specific examples thereof include phenyl, naphthyl, fluorenyl, anthracenyl, phenanthrenyl, biphenyl, and terphenyl. Furthermore, the aryl may be included in the category as long as it is a hydrocarbon ring moiety having at least one ring in which electrons are delocalized by alternating single and double bonds, i.e., conjugated π bonds, and may also include ring moieties fused with benzene, such as 1,2,3,4-tetrahydronaphthalenyl, 1,3-dihydroindenyl, and the like. Depending on the number of carbon atoms constituting the ring, C 6-15 Aryl, C 6-12 Aryl, C 6-10 Aryl, etc. are possible, but are not limited to these.

[0034] The term "multicyclic" refers to rings having more than one ring, including spiro rings, fused or condensed rings, or bridged rings.

[0035] The term "heteroaryl" refers to an aromatic heterocyclyl having one or more heteroatoms in the ring, which may include a single ring or multiple rings. Heteroaryl is, for example, thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine, pyrazolopyridine, triazolopyrimidine, triazolopyrimidine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, The heteroaryl may be a heterocyclic moiety such as, but is not limited to, benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole, dibenzofuran, pyrazolopyridine, etc. Furthermore, the heteroaryl may be included in the category as long as it is a heterocyclic moiety having at least one ring in which electrons are delocalized by alternating single bonds and double bonds, i.e., conjugated π bonds, and may also include a heterocyclic moiety fused with benzene, such as, for example, benzodioxolyl or dihydrobenzodioxinyl. In addition, heteroaryl can be, but is not limited to, 5-15 membered heteroaryl, 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-6 membered heteroaryl, 6-12 membered heteroaryl, 6-10 membered heteroaryl, etc. depending on the number of atoms constituting the ring.

[0036] The term "heterocycloalkyl" refers to a non-aromatic heterocyclyl having one or more heteroatoms in the ring, and may include a single ring or multiple rings. The heterocycloalkyl may include a saturated ring. Furthermore, the heterocycloalkyl may have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring, as long as the ring does not have aromaticity due to the presence of the double bonds. Depending on the number of atoms constituting the ring, possible examples include, but are not limited to, 3-15 membered heterocycloalkyl, 4-10 membered heterocycloalkyl, 4-8 membered heterocycloalkyl, 5-14 membered heterocycloalkyl, and 5-12 membered heterocycloalkyl. Heterocycloalkyls include, for example, aziridine, azetedine, pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, isoxazolidine, benzo[d]isoxazolidine, oxazinane, It may include heterocyclic residues such as azabicyclo[2,2,1]heptane, 2-azabicyclo[3.3]heptane, 5-oxa-6-azabicyclo[2.4]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1S,4S)-2-azabicyclo[2.2.2]octane, diazabicyclo[5.5]undecane, diazabicyclo[2.2.1]heptane, 2-azabicyclo[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1S,4S)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, etc., but It is not limited.

[0037] The term "heteroatom" means an atom other than carbon (C), and may specifically be a nitrogen (N), oxygen (O), or sulfur (S) atom. The heterocyclic ring, heteroaryl, and heterocycloalkyl mentioned above may contain one or more heteroatoms, for example, 1, 1 to 2, 1 to 3, or 1 to 4 heteroatoms.

[0038] The term "substitution" refers to replacing a hydrogen atom in a molecular structure with a substituent so as to result in a chemically stable compound from such substitution without exceeding the valence on the designated atom. For example, "group A is substituted with substituent B" or "group A has substituent B" may mean that a hydrogen atom bonded to an atom such as carbon constituting the skeleton of group A is replaced with substituent B, so that group A and substituent B form a covalent bond. Accordingly, a group that does not have a hydrogen atom that can leave is practically difficult or impossible to have a substituent, and when the present specification exemplifies a range of combinations of various groups and substituents including groups that are difficult to have substituents, combinations of groups and substituents that are obviously impossible to substituent should be interpreted as excluding from the range. Non-limiting examples of the substituents include halo (F, Cl, Br, I), C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, hydroxyl, C 1~10Alkoxy, amino, nitro, thiol, thioether, imine, cyano, phosphine, carboxy, carbamoyl, acetal, thiocarbonyl, sulfonyl, sulfonamide, ketone, aldehyde, ester, acetyl, amide, oxo(=0), haloalkyl (e.g., trifluoromethyl), substituted aminoacyl and aminoalkyl, carbocyclic cycloalkyl which is monocyclic or fused or non-fused multiple rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocycloalkyl which is monocyclic or fused or non-fused multiple rings (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), carbocyclic, heterocyclic, monocyclic, fused It may be at least one selected from the group consisting of polycyclic, non-fused polycyclic, fused polycyclic aryl or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuranyl), amino (primary, secondary or tertiary), aryl, aryloxy, and aryl-alkyl. In addition, each of the above-mentioned exemplified substituents may be optionally substituted with a substituent selected from these groups of substituents.

[0039] In the chemical structural formulas illustrated herein, the symbols for carbon atoms (C) and hydrogen atoms (H) may be omitted according to the conventional notation method of chemical structural formulas. For example, even if the symbols for hydrogen atoms are not indicated, it should be understood that a number of hydrogen atoms satisfying the valence of the carbon atoms (or heteroatoms) forming the skeleton are bonded to the carbon atoms (or heteroatoms). From this perspective, for example, When A and B in the structural formula are defined as being able to be carbon (C) or nitrogen (N) independently, this assumes that when C or N atoms are applied to the structural formula, a number of hydrogen atoms satisfying the valence can be further bonded. Therefore, it should be understood that specifically, A can be -CH2- or -NH-, and B can be =CH- or =N-.

[0040] In addition, when a polycyclic ring is depicted as having a substituent in the present specification and the carbon (or heteroatom) on which the substituent is positioned in the polycyclic ring is not specified, it should be understood that the substituent may be positioned on the carbon (or heteroatom) of any ring constituting the polycyclic ring. For example, when a substituent is depicted on one ring of a bicyclic ring and the carbon (or heteroatom) on which the substituent is positioned is not specified, it means that the substituent may be positioned not only on the corresponding ring but also on the carbon (or heteroatom) of another ring.

[0041]

[0042] tricyclic derivatives

[0043] One aspect of the present invention provides a compound represented by the following chemical formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0044] (I)

[0045] Here

[0046] X 1 and X 2are each independently N or C;

[0047] Y is O, S, C 1-4 Alkylene, C 1-3 Alkyleneoxy, C 1-3 Alkylenethiol, oxyC 1-3 Alkylene, or thioC 1-3 It is alkylene;

[0048] L is sulfonyl, C 1-6 Alkylene, or C 1-6 It is alkylenesulfonyl;

[0049] R 1 Silver C 6-15 Aryl, C 3-15 Cycloalkyl, 5-15 membered heteroaryl, or 3-15 membered heterocycloalkyl, wherein aryl, heteroaryl and heterocycloalkyl are each independently hydroxy, halogen, cyano, C 1-10 Alkyl, haloC 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkoxy-C 1-10 wherein said heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S and O, wherein said heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S and O;

[0050] R 2 is H, hydroxy, halogen, cyano, C 1-10 Alkyl, haloC 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkoxy-C 1-10 alkoxy, or acetyl;

[0051] A is C 1-6 Alkylene, C 1-6 Alkylenecarbonyl, or carbonyl;

[0052] B is H, hydroxy, C 1-10 Alkoxy, or C 1-10 It is alkylamino;

[0053] Z 1 , Z2 and Z 3 are each independently H, hydroxy, halogen, cyano, C 1-10 Alkyl, haloC 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkoxy-C 1-10 Alkoxy, or acetyl.

[0054] In another embodiment, the residue of the above formula (I) Is , , or and;

[0055] X 1 and X 2 are each independently N or C;

[0056] Y' is O or S;

[0057] m is an integer from 1 to 3.

[0058] In another implementation, X 1 and X 2 are each independently N or C;

[0059] Y is O, C 2-4 Alkylene, C 1-3 Alkyleneoxy, or oxyC 1-3 It is alkylene;

[0060] L is sulfonyl, C 1-6 Alkylene, or C 1-6 It is alkylenesulfonyl;

[0061] R 1 Silver C 6-12 Aryl, C 3-12 Cycloalkyl, 5-12 membered heteroaryl, or 3-12 membered heterocycloalkyl, wherein aryl, heteroaryl and heterocycloalkyl are each independently hydroxy, halogen, cyano, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6wherein said heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S and O, wherein said heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S and O;

[0062] R 2 is H or halogen;

[0063] A is C 1-6 alkylene or carbonyl;

[0064] B is H, hydroxy, C 1-6 Alkoxy, or C 1-6 It is alkylamino;

[0065] Z 1 , Z 2 and Z 3 are each independently H, hydroxy, halogen, C 1-6 Alkyl, or C 1-6 It is alkoxy.

[0066] In another implementation, R 1 silver , , , , , , , or And,

[0067] M is independently CH or N, and at least one M is N;

[0068] Q is independently NH, S, or O;

[0069] R A are each independently hydroxy, halogen, cyano, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Selected from the group consisting of alkoxy and acetyl;

[0070] n is an integer from 0 to 3.

[0071] In another implementation, X 1 and X 2 One of these is N and the other is C;

[0072] Y is O, C 2-4 alkylene, oxymethylene, or methyleneoxy;

[0073] L is sulfonyl or methylene;

[0074] R 1 is phenyl, 5-12 membered heteroaryl, or 5-12 membered heterocycloalkyl, wherein phenyl, heteroaryl and heterocycloalkyl are each independently hydroxy, halogen, cyano, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 wherein said heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S and O, wherein said heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S and O;

[0075] R 2 is H or halogen;

[0076] A is methylene or carbonyl;

[0077] B is H, hydroxy, methoxy, methylamino, or ethylamino;

[0078] Z 1 Silver H, Hydroxy, Halogen, C 1-6 Alkyl, or C 1-6 It is alkoxy;

[0079] Z 2 and Z 3 are each independently H, hydroxy, or C 1-6 It is alkoxy.

[0080] In another implementation, X 1 and X 2 One of these is N and the other is C;

[0081] Y is O, C 2-4 alkylene, oxymethylene, or methyleneoxy;

[0082] L is sulfonyl or methylene;

[0083] R 1 is phenyl, pyridyl, imidazolyl, furanyl, benzodioxolyl, dihydrobenzodioxinyl, benzothiophenyl, or indolyl, wherein phenyl, pyridyl, imidazolyl, furanyl, benzodioxolyl, dihydrobenzodioxinyl, benzothiophenyl, and indolyl each independently have or do not have one or more substituents selected from the group consisting of hydroxy, halogen, cyano, methyl, halomethyl, methoxy, methoxypropoxy, and acetyl;

[0084] R 2 is H or halogen;

[0085] A is methylene or carbonyl;

[0086] B is H, hydroxy, methoxy, methylamino, or ethylamino;

[0087] Z 1 is H, hydroxy, halogen, ethyl, or methoxy;

[0088] Z 2 and Z 3 are each independently H, hydroxy, or methoxy.

[0089] In another embodiment, the residue -AB of the above formula (I) is , , , , , , or am.

[0090] In another embodiment, the residue of the above formula (I) Is , , , , , or am.

[0091] In another implementation, R 1 silver , , , , , , , , , , , , , , , , , , , , , , , , , or am.

[0092] In specific examples, the scope of the present invention includes compounds selected from the group consisting of: or pharmaceutically acceptable salts or stereoisomers thereof.

[0093] 1> 1-(1-((3-fluorophenyl)sulfonyl)-1H-benzofuro[3,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0094] 2> 1-(1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0095] 3> N-methyl-1-(1-(phenylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine hydrochloride;

[0096] 4> N-methyl-1-(1-tosyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine hydrochloride;

[0097] 5> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine dihydrochloride;

[0098] 6> 1-(1-Benzyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0099] 7> 1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxamide;

[0100] 8> 1-(1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine hydrochloride;

[0101] 9> 1-((3-fluorophenyl)sulfonyl)-3-(methoxymethyl)-4,5-dihydro-1H-benzo[g]indole;

[0102] 10> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanamine dihydrochloride;

[0103] 11> 1-(7-ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine hydrochloride;

[0104] 12> 1-(1-((3-fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine;

[0105] 13> 1-((3-fluorophenyl)sulfonyl)-3-((methylamino)methyl)-4,5-dihydro-1H-benzo[g]indol-7-ol;

[0106] 14> 1-(1-((3-fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine;

[0107] 15> 1-((3-fluorophenyl)sulfonyl)-3-((methylamino)methyl)-4,5-dihydro-1H-benzo[g]indol-8-ol;

[0108] 16> 1-(1-((3-fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine;

[0109] 17> 1-(1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0110] 18> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine;

[0111] 19> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine fumarate;

[0112] 20> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine dihydrochloride;

[0113] 21> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine 2-hydroxysuccinate;

[0114] 22> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine 2,3-dihydroxysuccinate;

[0115] 23> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine difumarate;

[0116] 24> N-Methyl-1-(1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine hydrochloride;

[0117] 25> 1-(1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0118] 26> 1-(1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0119] 27> N-methyl-1-(1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine;

[0120] 28> 1-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0121] 29> 1-(1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0122] 30> 1-(1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0123] 31> 1-(1-(Benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0124] 32> 1-(1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0125] 33> 1-(1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0126] 34> 1-(1-(Benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0127] 35> 1-(1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0128] 36> 1-(1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0129] 37> 1-(1-((3,4-dimethylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine;

[0130] 38> 1-(1-((6-methoxypyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine;

[0131] 39> N-((1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methyl)ethanamine;

[0132] 40> 1-(1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0133] 41> 3-((3-((methylamino)methyl)-5,6-dihydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-1(4H)-yl)sulfonyl)phenol hydrochloride;

[0134] 42> N-Methyl-1-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine fumarate;

[0135] 43> N-methyl-1-(1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine;

[0136] 44> 1-(8-chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0137] 45> 1-(8-chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine;

[0138] 46> 1-(1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0139] 47> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)methanamine dihydrochloride;

[0140] 48> 1-(1-((3-methoxyphenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0141] 49> 3-((3-((methylamino)methyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-1-yl)sulfonyl)phenol hydrochloride;

[0142] 50> 1-(1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0143] 51> 1-(1-((3-fluorophenyl)sulfonyl)-6,7-dihydro-5H-benzo[c]pyrrolo[1,2-a]azepin-3-yl)-N-methylmethanamine hydrochloride;

[0144] 52> N-Methyl-1-(1-(pyridin-2-ylsulfonyl)-6,7-dihydro-5H-benzo[c]pyrrolo[1,2-a]azepin-3-yl)methanamine dihydrochloride;

[0145] 53> 2-Chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde;

[0146] 54> Methyl 1-((3-cyanophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate;

[0147] 55> Methyl 1-((3-acetylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate; and

[0148] 56> (1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol.

[0149] The compound of formula (I) of the present invention may exist in the form of a pharmaceutically acceptable salt. Accordingly, the scope of the compound of the present invention includes a pharmaceutically acceptable salt of the compound represented by formula (I). As used herein, the term "pharmaceutically acceptable salt" means any organic or inorganic acid addition salt of the compound represented by formula (I) at a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and the side effects due to the salt do not reduce the beneficial effects of the compound represented by formula (I).

[0150] In particular, the pharmaceutically acceptable salt may be an acid addition salt formed by a free acid. Here, the acid addition salt can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.; non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.; organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.

[0151] Such pharmaceutically acceptable salts may include sulfate, sulfite, nitrate, phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, benzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, glycolate, malate, tartrate, mandelate, and the like.

[0152] The above acid addition salt can be prepared by a conventional method, for example, by dissolving the derivative of the chemical formula (I) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, ethyl acetate, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess of acid under reduced pressure, drying, and crystallizing in an organic solvent.

[0153] In addition, the pharmaceutically acceptable salt may be a salt or metal salt obtained using a base. As an example of a metal salt, an alkali metal or alkaline earth metal salt can be obtained by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. As an alkali metal salt, sodium, potassium, or calcium salts may be pharmaceutically suitable. In addition, a corresponding salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0154] As used herein, "stereoisomer" means a compound having the same chemical formula or molecular formula but being sterically different. As used herein, stereoisomers include enantiomers, diastereomers, cis / trans isomers, rotamers, and atropisomers, and each of these isomers and mixtures thereof are also included in the scope of the present invention. For example, since the chemical formula (I) of the present invention does not specify a stereochemical structure, it may include the stereoisomers of the chemical formula (I). Specifically, in the chemical structural formula, a solid bond (ㅡ) connected to an asymmetric carbon atom represents a wedge-shaped solid bond ( ) and wedge-shaped dotted line combination ( ) may be included. It should also be construed that stereoisomers of the exemplary compounds described herein are also included in the scope of the present invention.

[0155] Additionally, the compounds of the present invention may include hydrates and solvates of the compound of the above formula (I). The hydrates and solvates may be prepared using known methods, and are preferably non-toxic and water-soluble. In particular, the hydrates and solvates may preferably be those in which 1 to 5 molecules of water and an alcoholic solvent (particularly, ethanol, etc.) are combined, respectively.

[0156] Additionally, the compounds of the present invention may include metabolites of the compounds of formula (I). The compounds of the present invention may be formed into metabolites in vivo upon administration, and specifically, such metabolites may be produced from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, etc. of the administered compound. For example, compounds produced by a method comprising a step of contacting a mammal with a compound of the present invention for a period of time sufficient to obtain metabolites of the compound of the present invention may also fall within the scope of the present invention.

[0157] The compounds of the present invention may also include prodrugs of the compounds of formula (I), which themselves have little or no pharmacological activity, but which, when administered internally, can be converted into compounds having the desired activity, for example, by hydrolysis. Such prodrugs may be derivatives of the compounds containing a biologically reactive functional group, wherein the biologically reactive functional group can be cleaved from the compound or otherwise reacted under biological conditions (in vivo or in vitro) to provide the compound. Typically, the prodrug is inactive, or at least has a lower activity than the compound, which allows the compound to exhibit its activity after cleavage from the biologically reactive functional group. The biologically reactive functional group can be hydrolyzed or oxidized under biological conditions to produce the compound. For example, the prodrug may contain a biologically hydrolyzable group. Examples of biologically hydrolyzable groups include, but are not limited to, biologically hydrolyzable phosphates, biologically hydrolyzable esters, biologically hydrolyzable amides, biologically hydrolyzable carbonic esters, biologically hydrolyzable carbamates, and biologically hydrolyzable ureides.

[0158]

[0159] Uses of tricyclic derivatives

[0160] Another aspect of the present invention provides a pharmaceutical use of a compound represented by the above formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0161] The compound of formula (I) according to the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, may have a reversible proton pump inhibitory effect. Specifically, the compound of formula (I) according to the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, may inhibit H present in activated gastric parietal cells. + / K+ K of ATPase + H competitively binds to the binding site + It can have the effect of reducing gastric acid secretion by interfering with the exchange process.

[0162] Accordingly, the present invention provides a potassium-competitive acid blocker (P-CAB) comprising a compound of the above formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof as an active ingredient. The present invention also provides an acid pump antagonist comprising a compound of the above formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof as an active ingredient.

[0163] The present invention also provides a method for reversible proton pump inhibition comprising the step of treating a sample or cell with a compound of the above formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0164] In this way, the compound of the above chemical formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, can be used to prevent or treat diseases related to gastric acid secretion.

[0165] Here, “prevention” means any action that inhibits or delays the occurrence, spread, and recurrence of the disease by administering the compound, and “treatment” means any action that improves or beneficially changes the symptoms of the disease by administering the compound.

[0166] Accordingly, the present invention provides a use of a compound represented by the above chemical formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, for preventing or treating a disease related to gastric acid secretion.

[0167] The present invention also provides a use of a compound represented by the above chemical formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, for the manufacture of a medicament for preventing or treating a disease related to gastric acid secretion.

[0168] The present invention also provides a method for preventing or treating a disease related to gastric acid secretion, comprising administering a compound represented by the above chemical formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need thereof.

[0169] Here, the term "subject in need" refers to all animals, including monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, guinea pigs, and the like, including humans (patients) who have developed or may develop the above-mentioned disease, and may specifically refer to mammals. In addition, the above-mentioned subject in need may also refer to a biological sample.

[0170] 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 may be administered through any general route, such as oral or parenteral, as long as it can reach the target tissue.

[0171] The present invention also provides a pharmaceutical composition comprising a compound of the above formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, as an active ingredient.

[0172] The present invention also provides a pharmaceutical composition for treating or preventing a disease related to gastric acid secretion, comprising a compound of the above formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof as an active ingredient.

[0173] The above-mentioned disease related to gastric acid secretion may be, for example, a disease caused by excessive secretion of gastric acid. Diseases caused by excessive secretion of gastric acid include gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0174] As specific examples, diseases related to the above gastric acid secretion include gastrointestinal diseases, dyspepsia, functional dyspepsia, gastroesophageal diseases, gastroesophageal reflux disease, erosive gastroesophageal reflux disease, maintenance therapy after treatment of erosive gastroesophageal reflux disease, non-erosive gastroesophageal reflux disease, gastritis, esophagitis, reflux esophagitis, peptic ulcer, gastric ulcer, duodenal ulcer, ulcer induced by nonsteroidal anti-inflammatory drugs (NSAIDs), ulcer induced by administration of drugs other than NSAIDs (aspirin, clopidogrel, etc.), alcoholic ulcer, stress-induced hyperacidity and ulcer, Helicobacter pylori (H. pylori) infection, Zollinger-Ellison syndrome, gastric cancer, and hyperacidity.

[0175] The pharmaceutical composition may include conventional, non-toxic, pharmaceutically acceptable additives incorporated into the formulation according to conventional methods. Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the above formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, as an active ingredient, and a pharmaceutically acceptable additive.

[0176] For example, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0177] Examples of additives used in the above pharmaceutical composition 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.

[0178] The above pharmaceutical composition may 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).

[0179] For example, the pharmaceutical composition may be formulated as a preparation for oral administration, and the additives used in this case may 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. Specifically, solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations may be formulated by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used. In addition, liquid preparations for oral administration may include suspensions, 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.

[0180] 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.

[0181] The compound or composition of the present invention may be administered to a patient in a therapeutically effective amount or a pharmaceutically effective amount.

[0182] The term "therapeutically effective amount" as used herein refers to an amount of a compound represented by the above formula (I) that is effective in treating or preventing a disease. Specifically, a "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined based on factors including the subject type, severity, age, sex, type of disease, activity of the drug, sensitivity to the drug, time of administration, route of administration, excretion rate, duration of treatment, concurrently used drugs, or other factors well known in the medical field.

[0183] 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.

[0184]

[0185] [Example]

[0186] The present invention is described in more detail below by way of examples. However, the following examples are intended only to illustrate the present invention, and the scope of the present invention is not limited to these examples.

[0187]

[0188] The meanings of the abbreviations described in the examples below are as follows.

[0189] - AcOH: acetic acid

[0190] - ACN or MeCN: Acetonitrile

[0191] - AlCl3: Aluminum chloride

[0192] - BBr3: Boron tribromide

[0193] - Brine: saturated sodium chloride solution

[0194] - CuI: Copper iodide

[0195] - DBU: 1,8-diazabicyclo[5,4,0]undec-7-ene

[0196] - DIBAL-H: Diisobutyl aluminum hydride solution

[0197] - DIPEA: N,N-diisopropylethylamine

[0198] - DCM or MC: Dichloromethane

[0199] - DMAP: 4-dimethylaminopyridine

[0200] - DMF: N,N-dimethylformamide

[0201] - EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0202] - EtOAc or EA: ethyl acetate

[0203] - EtOH: ethanol

[0204] - Et2O: ether

[0205] - EtNH2: Ethylamine

[0206] - Hex: n-hexane

[0207] - i-PrOH: Isopropyl alcohol

[0208] - K2CO3: Potassium carbonate

[0209] - MeOH: methanol

[0210] - Na: Sodium

[0211] - NaOMe: sodium methoxide

[0212] - NaOEt: sodium ethoxide

[0213] - NaOH: sodium hydroxide

[0214] - NaBH4: sodium borohydride

[0215] - Na2SO4: sodium sulfate

[0216] - NBS: N-bromosuccinimide

[0217] - NH4Cl: Ammonium chloride

[0218] - NMO: N-methylmorpholine-N-oxide

[0219] - Pd(OAc)2: Palladium acetate

[0220] - Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0)

[0221] - PhI(OAc)2: (diacetoxyiodo)benzene

[0222] - POCl3: phosphorus oxychloride

[0223] - TEA: Triethylamine

[0224] - TEMPO: 2,2,6,6-tetramethylpiperidine 1-oxyl

[0225] - THF: Tetrahydrofuran

[0226] - TPAP: Tetrapropylammonium perruthenate

[0227] - RT or rt: room temperature

[0228]

[0229] NMR spectra were recorded on a JNM-ECZ500R / S1 (500 MHz 1 H, Jeol) was measured and the results were reported as ppm values. The mass spectrum was H-Class_QDa (ESI + or ESI - , Waters). Purification was performed using the Isolera system and the Selekt purification system (Biotage). The column was separated using a normal silica gel or amino silica gel column (EtOAc / Hex or DCM / MeOH mobile phase condition) or a reversed-phase silica gel column (ACN / water mobile phase condition), as appropriate. Microwave experiments were performed using Monowave 400 (Anton Paar).

[0230]

[0231] [Example 1] 1-(1-((3-fluorophenyl)sulfonyl)-1H-benzofuro[3,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (8)

[0232]

[0233] Step 1: 1H-Benzofuro[3,2-b]pyrrole (3)

[0234] Benzofuran-2-carbaldehyde (210 mg, 1.5 mmol) and azidoacetate (387 mg, 3.0 mmol) were dissolved in EtOH (10 mL), and NaOEt (3.0 mmol, Na 69 mg in 1 mL EtOH) was added. After stirring for 1 h, NH4Cl solution was added, and filtered to obtain a yellow solid. This yellow solid was dissolved in toluene (10 mL) and refluxed for 30 min. After removing the solvent, recrystallization from EtOH was performed to synthesize 120 mg of crude pyrrole ester. This material was dissolved in EtOH (4 mL) and water (4 mL), and 10% NaOH aqueous solution (2 mL) was added and stirred. After 12 h, the reaction was terminated with 1 N HCl, and extracted three times with EtOAc to synthesize 82 mg of crude compound. This substance was dissolved in ethylene glycol (4 mL), NaOH (0.1 g) was added, and stirred at 120°C for 1 hour. After cooling to room temperature, NH4Cl solution was added to terminate the reaction, extracted with EtOAc, and dried / filtered over MgSO4. The organic layer was dried under reduced pressure and separated by silica gel column chromatography (EtOAc:Hex = 1:2) to obtain 1H-benzofuro[3,2-b]pyrrole (white solid 52 mg, yield 22%).

[0235] 1 H NMR (500 MHz, CDCl3) δ 8.07 (br, 1H), 7.41 (m, 2H), 7.11 (m, 2H), 6.77 (t,J= 3.0 Hz, 1H), 6.18 (q,J= 1.5 Hz, 1H)

[0236]

[0237] Step 2: 1H-Benzofuro[3,2-b]pyrrole-3-carbaldehyde (4)

[0238] 1H-Benzofuro[3,2-b]pyrrole (50 mg, 0.32 mmol) and DMF (36 μL, 0.48 mmol) were dissolved in 1,2-dichloroethane (4 mL), and POCl3 (36 μL, 0.38 mmol) was added at 0°C. After stirring at the same temperature for 30 min, the mixture was heated to 80°C for 1 h, cooled to room temperature, and 1N NaOH solution was added to terminate the reaction. The reaction mixture was extracted with CH2Cl2, dried over MgSO4, and filtered. The organic layer was dried under reduced pressure and separated by silica gel column chromatography (EtOAc:Hex = 1:2) to obtain 1H-benzofuro[3,2-b]pyrrole-3-carbaldehyde (47 mg of white solid, yield 79%).

[0239] 1 H NMR (500 MHz, CDCl3) δ 10.1 (br, 1H), 9.6 (s, 1H), 7.78 (d,J= 8.0 Hz, 1H), 7.56 (d,J= 9.0 Hz, 1H), 7.41 (dt,J= 7.0, 1.5 Hz, 1H), 7.39 (t,J= 6.5 Hz, 1H), 6.90 (d,J= 2.0 Hz, 1H)

[0240]

[0241] Step 3: 1-((3-fluorophenyl)sulfonyl)-1H-benzofuro[3,2-b]pyrrole-3-carbaldehyde (6)

[0242] 1H-Benzofuro[3,2-b]pyrrole-3-carbaldehyde (230 mg, 1.24 mmol) was dissolved in DMF (6 mL), and NaH (60% in mineral oil, 74 mg, 1.86 mmol) was added at 0°C. After stirring at the same temperature for 30 minutes, 3-fluorobenzenesulfonyl chloride (0.25 mL, 1.86 mmol) was added, and the mixture was stirred at room temperature for 2 hours. NH4Cl aqueous solution was added to the reaction solution to terminate the reaction, and the reaction solution was diluted with EtOAc and washed three times with NH4Cl aqueous solution. The organic layer was dried over MgSO4, filtered, dried under reduced pressure, and separated by silica gel column chromatography (EtOAc:Hex = 1:2) to obtain 1-((3-fluorophenyl)sulfonyl)-1H-benzofuro[3,2-b]pyrrole-3-carbaldehyde (brown solid, 260 mg, yield 61%).

[0243] 1 H NMR (500 MHz, CDCl3) δ 10.1 (s, 1H), 8.27 (dd,J= 7.5, 1.0 Hz, 1H), 7.61 (d,J= 8.0 Hz, 1H), 7.50 (m, 2H), 7.40 (m, 3H), 7.23 (dt,J= 8.5, 2.0 Hz, 1H), 6.90 (d,J= 2.0 Hz, 1H)

[0244]

[0245] Step 4: 1-(1-((3-fluorophenyl)sulfonyl)-1H-benzofuro[3,2-b]pyrrol-3-yl)-N-methylmethanamine (7)

[0246] 1-((3-Fluorophenyl)sulfonyl)-1H-benzofuro[3,2-b]pyrrole-3-carbaldehyde (81 mg, 0.23 mmol) was dissolved in MeOH (6 mL), and CH3NH2 (0.5 mL, excess) was added at 0°C. After stirring at room temperature for 12 h, NaBH4 (25 mg, 0.69 mmol) was added at 0°C, and stirred at room temperature for another 12 h. NH4Cl aqueous solution was added to the reaction solution to terminate the reaction, and the reaction solution was extracted three times with EtOAc. The organic layer was dried over MgSO4, filtered, dried under reduced pressure, and separated by silica gel column chromatography (CH2Cl2:MeOH = 20:1) to obtain 1-(1-((3-fluorophenyl)sulfonyl)-1H-benzofuro[3,2-b]pyrrol-3-yl)-N-methylmethanamine (40 mg of brown liquid, yield 48%).

[0247] 1 H NMR (500 MHz, MeOH-d4) δ 8.02 (dd,J= 7.5, 1.0 Hz, 1H), 7.53 (dq,J= 7.5, 0.5 Hz, 1H), 7.47 (dt,J= 8.0, 2.0 Hz, 1H), 7.40 (m, 2H), 7.25 (m, 3H), 6.49 (s, 1H), 3.89 (s, 2H), 2.26 (s, 3H)

[0248]

[0249] Step 5: 1-(1-((3-fluorophenyl)sulfonyl)-1H-benzofuro[3,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (8)

[0250] 1-(1-((3-Fluorophenyl)sulfonyl)-1H-benzofuro[3,2-b]pyrrol-3-yl)-N-methylmethanamine (50 mg) was dissolved in CH3CN (3 mL), and HCl (2.0 M in Et2O, 0.3 mL) was added at room temperature. The reaction solution was heated to 80°C and filtered after 1 hour to obtain 1-(1-((3-fluorophenyl)sulfonyl)-1H-benzofuro[3,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (white solid 34 mg, yield 61%).

[0251] 1 H NMR (500 MHz, MeOH-d4) δ 8.11 (dd,J= 7.0, 2.0 Hz, 1H), 7.62 (dd,J= 12.5, 7.0 Hz, 2H), 7.48 (m, 2H), 7.34 (m, 3H), 6.90 (s, 1H), 4.54 (s, 2H), 2.73 (s, 3H); MS m / z 357 (MH - - HCl)

[0252]

[0253] [Example 2] 1-(1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (19)

[0254]

[0255] Step 1: Chroman-4-one oxime (11)

[0256] Chroman-4-one (5 g, 1 eq), hydroxylamine HCl (2.58 g, 1.1 eq), and sodium acetate (4.15 g, 1.5 eq) were dissolved in ethanol / H2O (1:1, 205 mL, 0.17 M), heated to 90°C, and stirred for 20 h. After lowering the temperature to room temperature, EtOAc was added to the reaction solution, diluted, and washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain chroman-4-one oxime. The synthesized compound was used in the next reaction without any additional purification process (5.56 g of white solid, crude).

[0257] 1H NMR (500 MHz, DMSO-d6) δ 11.24 (s, 1 H), 7.78 (dd,J=7.73, 1.43 Hz, 1 H), 7.25 (ddd,J=8.45, 7.02, 1.72 Hz, 1 H), 6.91 - 6.97 (m, 1 H), 6.86 - 6.91 (m, 1 H), 4.17 (t,J=6.01 Hz, 2 H), 2.82 (t,J=6.01 Hz, 2 H); MH + 164

[0258]

[0259] Step 2: Methyl 3-((chroman-4-ylideneamino)oxy)acrylate (13)

[0260] Chroman-4-one oxime (5.5 g, 1 eq) was dissolved in DMSO (33.7 mL, 1 M), and TEA (4.70 mL, 1 eq) was slowly added at room temperature. Methyl propiolate (6.0 mL, 2 eq) was dissolved in DMSO (13.5 mL, 2.5 M), and slowly added, and the mixture was heated to 70°C. After stirring at 70°C for 30 min, the temperature was lowered to room temperature. DCM was added to the reaction solution, diluted, and washed several times with distilled water and then brine. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 3-((chroman-4-ylideneamino)oxy)acrylate (yellow solid 7.09 g, two-step yield 85%).

[0261] 1H NMR (500 MHz, DMSO-d6) for the major (E)-isomer δ 8.02 (d,J=12.03 Hz, 1 H), 7.90 (dd,J=8.02, 1.72 Hz, 1 H), 7.37 - 7.44 (m, 1 H), 6.99 - 7.05 (m, 1 H), 6.95 - 6.99 (m, 1 H), 5.73 (d,J=12.60 Hz, 1 H), 4.25 (t,J=6.30 Hz, 2 H), 3.65 (s, 3 H), 3.04 (t,J=6.30 Hz, 2 H), Partial 1 H NMR for the minor (Z)-isomer δ 7.81 (dd,J=8.02, 1.72 Hz, 1 H), 7.61 (d,J=7.45 Hz, 1 H), 7.37 - 7.43 (m, 1 H), 6.99 - 7.03 (m, 1 H), 6.95 - 6.99 (m, 1 H), 4.99 (d,J=6.87 Hz, 1 H), 4.27 - 4.30 (m, 2 H), 3.62 (s, 3 H), 3.09 (t,J=6.01 Hz, 2 H); MH + 248

[0262]

[0263] Step 3: Methyl 1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxylate (14)

[0264] Methyl 3-((chroman-4-ylideneamino)oxy)acrylate (700 mg, 1 eq) was dissolved in 1,4-dioxane (18.87 mL, 0.15 M), DBU (0.42 mL, 1 eq) was added, and the mixture was heated in a microwave at 150°C for 30 min. EtOAc was added to the reaction solution to dilute it, and the mixture was washed several times with distilled water and then brine. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give methyl 1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxylate (ivory solid, 614 mg, yield 69%).

[0265] 1 H NMR (500 MHz, DMSO-d6) δ 12.16 (br s, 1 H), 7.55 (s, 1 H), 7.44 (dd,J=7.45, 1.72 Hz, 1 H), 7.05 (td,J=7.73, 1.72 Hz, 1 H), 6.91 (td,J=7.45, 1.15 Hz, 1 H), 6.83 (d,J=8.02 Hz, 1 H), 5.45 (s, 2 H), 3.72 (s, 3 H); MH + 230

[0266]

[0267] Step 4: Methyl 1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxylate (15)

[0268] Methyl 1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxylate (440 mg, 1 eq) and DMAP (50 mg, 0.2 eq) were dissolved in MeCN (2.56 mL, 0.75 M), 3-fluorobenzenesulfonyl chloride (0.28 mL, 1.1 eq) and DIPEA (0.67 mL, 2 eq) were added, and the mixture was stirred at room temperature for 5 h. Then, 3-fluorobenzenesulfonyl chloride (0.076 mL, 0.3 eq) was additionally added, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4, and then filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxylate (brown solid, 690 mg, yield 92%).

[0269] 1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1 H), 7.83 - 7.90 (m, 2 H), 7.61 - 7.74 (m, 3 H), 7.15 - 7.21 (m, 1 H), 7.01 (td,J=7.59, 1.43 Hz, 1 H), 6.92 (dd,J=8.02, 1.15 Hz, 1 H), 5.25 (s, 2 H), 3.81 (s, 3 H); MH + 388

[0270]

[0271] Step 5: (1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanol (16)

[0272] Methyl 1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxylate (690 mg, 1 eq) was dissolved in THF (8.91 mL, 0.2 M) and the temperature was lowered to 0℃. 1M DIBAL-H in toluene (5.43 mL, 3 eq) was added and stirred at 0℃ for 40 minutes. The reaction was quenched by adding 1N HCl aqueous solution, diluted with ethyl acetate, and washed several times with distilled water and saturated aqueous potassium sodium tartrate solution. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanol. The synthesized compound was used in the following reaction without a separate purification process (660 mg of brown solid, crude).

[0273] 1H NMR (500 MHz, DMSO-d6) δ 7.88 (dd,J=8.02, 1.15 Hz, 1 H), 7.52 - 7.67 (m, 3 H), 7.47 - 7.51 (m, 1 H), 7.45 (s, 1 H), 7.14 (td,J=7.73, 1.72 Hz, 1 H), 6.97 - 7.03 (m, 1 H), 6.90 (dd,J=8.02, 1.15 Hz, 1 H), 5.07 (t,J=5.44 Hz, 1 H), 5.03 (s, 2 H), 4.36 (d,J=5.16 Hz, 2 H); MH + 360

[0274]

[0275] Step 6: 1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (17)

[0276] (1-((3-Fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanol (540 mg, 1 eq) was dissolved in DCM (6.85 mL, 0.26 M), TEMPO (83.5 mg, 0.3 eq) and PhI(OAc)2 (918 mg, 1.6 eq) were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction was terminated by adding saturated aqueous NaHCO3 solution, diluted with DCM, and washed with distilled water and brine. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (pale pink solid, 540 mg, two-step yield 84%).

[0277] 1H NMR (500 MHz, MeOH-d4) δ 9.89 (s, 1 H), 8.39 (s, 1 H), 8.07 (dd,J=8.02, 1.72 Hz, 1 H), 7.53 - 7.63 (m, 3 H), 7.41 - 7.47 (m, 1 H), 7.14 - 7.19 (m, 1 H), 6.96 - 7.01 (m, 1 H), 6.88 (dd,J=8.02, 1.15 Hz, 1 H), 5.24 (s, 2 H); MH + 358

[0278]

[0279] Step 7: 1-(1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine (18)

[0280] 1-((3-Fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (300 mg, 1 eq) was dissolved in MeOH (4.20 mL, 0.2 M), and a 2 M methylamine solution in MeOH (1.05 mL, 2.5 eq) was added. The mixture was stirred at room temperature for 1 hour. After lowering the temperature to 0°C, NaBH4 (16 mg, 0.5 eq) was added and stirred at room temperature for 1 hour and 30 minutes. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by amine column chromatography to obtain 1-(1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine (orange oil 265 mg, yield 84%).

[0281] 1H NMR (500 MHz, MeOH-d4) δ 8.05 (dd,J=7.73, 1.43 Hz, 1 H), 7.42 - 7.51 (m, 3 H), 7.32 - 7.40 (m, 2 H), 7.13 (td,J=7.73, 1.72 Hz, 1 H), 6.99 (td,J=7.73, 1.15 Hz, 1 H), 6.88 (dd,J=8.31, 1.43 Hz, 1 H), 4.97 (s, 2 H), 3.56 (s, 2 H), 2.36 (s, 3 H); MH + 373

[0282]

[0283] Step 8: 1-(1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (19)

[0284] 1-(1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine (120 mg, 1 eq) was dissolved in ethyl acetate (3.22 mL, 0.1 M) and cooled to 0°C. 1 M HCl in EtOAc (0.64 mL, 2.0 eq) was added at 0°C, cooled to room temperature, and stirred at room temperature for 30 min. The resulting solid was filtered with ethyl acetate to obtain 1-(1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (pale ivory solid, 98 mg, yield 74%).

[0285] 1H NMR (500 MHz, MeOH-d4) δ 8.08 (dd,J=7.73, 1.43 Hz, 1 H), 7.79 (s, 1 H), 7.48 - 7.56 (m, 2 H), 7.37 - 7.46 (m, 2 H), 7.15 - 7.20 (m, 1 H), 6.98 - 7.04 (m, 1 H), 6.91 (dd,J=8.02, 1.15 Hz, 1 H), 5.03 (s, 2 H), 4.11 (s, 2 H), 2.72 (s, 3 H); MS m / z 373 (MH + - HCl)

[0286]

[0287] [Example 3] N-methyl-1-(1-(phenylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine hydrochloride (25)

[0288]

[0289] Step 1: (1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanol (20)

[0290] Methyl 1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxylate (1.42 g, 1 eq) was dissolved in THF (62 mL, 0.1 M) and the temperature was lowered to 0℃. 1M DIBAL-H in toluene (18.58 mL, 3 eq) was added and stirred at 0℃ for 20 minutes. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water and a saturated aqueous solution of potassium sodium tartrate. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanol. The synthesized compound was used in the next reaction without any separate purification (1.4 g, crude tan solid).

[0291] 1H NMR (500 MHz, MeOH-d4) δ 7.26 (dd,J=7.45, 1.72 Hz, 1 H), 6.94 - 6.99 (m, 1 H), 6.85 (td,J=7.45, 1.15 Hz, 1 H), 6.79 (dd,J=8.02, 1.15 Hz, 1 H), 6.76 (s, 1 H), 5.34 (s, 2 H), 4.46 (s, 2 H); MH + 202

[0292]

[0293] Step 2: 1,4-Dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (21)

[0294] (1,4-Dihydrochromeno[4,3-b]pyrrol-3-yl)methanol (1.23 g, 1 eq) was dissolved in MeCN (30.56 mL, 0.2 M), and molecular sieve 4Å (3.57 g) was added and dried. N-Methylmorpholine N-oxide (1.0 g, 1.5 eq) and TPAP (322 mg, 0.15 eq) were added and stirred at room temperature for 6 h. The temperature was then increased to 30°C and stirred for 40 min. After lowering the temperature to room temperature, Celite was used. ® The organic layer was filtered and washed with EtOAc, then distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (400 mg of black solid, 32% yield in two steps).

[0295] 1 H NMR (500 MHz, MeOH-d4) δ 9.69 (s, 1 H), 7.62 (s, 1 H), 7.33 (dd,J=7.45, 1.72 Hz, 1 H), 7.07 (td,J=7.88, 1.43 Hz, 1 H), 6.90 (td,J=7.45, 1.15 Hz, 1 H), 6.83 (dd,J=8.02, 1.15 Hz, 1 H), 5.51 (s, 2 H); MH+ 200

[0296]

[0297] Step 3: 1-(Phenylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (23)

[0298] 60% sodium hydride (37 mg, 1.5 eq) in mineral oil was dissolved in DMF (1.5 mL, 0.4 M), then 1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (140 mg, 1 eq) dissolved in DMF (1.5 mL, 0.4 M) was slowly added, and the mixture was stirred at room temperature for 40 minutes. Benzenesulfonyl chloride (0.06 mL, 1.1 eq) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction was stopped by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4, and then filtered under reduced pressure. The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography, washed with diethyl ether, and purified once more to obtain 1-(phenylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (ivory solid, 85 mg, yield 41%).

[0299] 1 H NMR (500 MHz, MeOH-d4) δ 9.88 (s, 1 H), 8.39 (s, 1 H), 8.08 (dd,J=7.73, 1.43 Hz, 1 H), 7.78 - 7.81 (m, 2 H), 7.63 - 7.68 (m, 1 H), 7.50 - 7.55 (m, 2 H), 7.13 (td,J=7.73, 1.15 Hz, 1 H), 6.95 (td,J=7.73, 1.72 Hz, 1 H), 6.85 (dd,J=8.31, 1.43 Hz, 1 H), 5.24 (s, 2 H); MH + 340

[0300]

[0301] Step 4: N-Methyl-1-(1-(phenylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine (24)

[0302] 1-(Phenylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (85 mg, 1 eq) was dissolved in MeOH (1.25 mL, 0.2 M), and a 2 M methylamine solution in MeOH (0.31 mL, 2.5 eq) was added. The mixture was stirred at room temperature for 2 h. After cooling to 0°C, NaBH4 (4.7 mg, 0.5 eq) was added and stirred at room temperature for 30 min. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain N-methyl-1-(1-(phenylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine (yellow sticky oil 86 mg, yield 96%).

[0303] 1 H NMR (500 MHz, MeOH-d4) δ 8.07 (dd,J=7.73, 1.43 Hz, 1 H), 7.64 (dd,J=8.59, 1.15 Hz, 2 H), 7.56 - 7.60 (m, 1 H), 7.49 (s, 1 H), 7.41 - 7.46 (m, 2 H), 7.11 (td,J=7.73, 1.15 Hz, 1 H), 6.96 (td,J=7.73, 1.15 Hz, 1 H), 6.85 (dd,J=8.02, 1.15 Hz, 1 H), 4.97 (s, 2 H), 3.58 (s, 2) H), 2.38 (s, 3 H); MH + 355

[0304]

[0305] Step 5: N-Methyl-1-(1-(phenylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine hydrochloride (25)

[0306] N-Methyl-1-(1-(phenylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine (80 mg, 1 eq) was dissolved in ethyl acetate (2.26 mL, 0.1 M) and the mixture was cooled to 0°C. 1 M HCl in EtOAc (0.45 mL, 2.0 eq) was added at 0°C, the mixture was cooled to room temperature, and the mixture was stirred at room temperature for 40 min. The resulting solid was filtered with ethyl acetate to obtain N-methyl-1-(1-(phenylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine hydrochloride (gray solid 88 mg, 100% quantitative).

[0307] 1 H NMR (500 MHz, MeOH-d4) δ 8.10 (dd,J=8.02, 1.72 Hz, 1 H), 7.78 (s, 1 H), 7.69 (dd,J=8.59, 1.15 Hz, 2 H), 7.60 - 7.65 (m, 1 H), 7.45 - 7.50 (m, 2 H), 7.12 - 7.17 (m, 1 H), 6.98 (td,J=7.73, 1.15 Hz, 1 H), 6.88 (dd,J=8.02, 1.15 Hz, 1 H), 5.03 (s, 2 H), 4.09 (s, 2 H), 2.71 (s, 3H); MS m / z 355 (MH + - HCl)

[0308]

[0309] [Example 4] N-methyl-1-(1-tosyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine hydrochloride (29)

[0310]

[0311] Step 1: 1-Tosyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (27)

[0312] 60% sodium hydride (26.2 mg, 1.5 eq) in mineral oil was dissolved in DMF (1.09 mL, 0.4 M), then 1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (100 mg, 1 eq) dissolved in DMF (1.09 mL, 0.4 M) was slowly added and stirred at room temperature for 30 minutes. 4-Methylbenzenesulfonyl chloride (91 mg, 1.1 eq) was added and stirred at room temperature for 20 minutes. The reaction was terminated by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-tosyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (110 mg of beige solid, yield 71%).

[0313] 1 H NMR (500 MHz, MeOH-d4) δ 9.87 (s, 1 H), 8.36 (s, 1 H), 8.10 (dd,J=7.73, 1.43 Hz, 1 H), 7.67 (d,J=8.02 Hz, 2 H), 7.33 (d,J=8.02 Hz, 2 H), 7.11 - 7.16 (m, 1 H), 6.95 (td,J=7.59, 1.43 Hz, 1 H), 6.85 (dd,J=8.02, 1.15 Hz, 1 H), 5.24 (s, 2 H), 2.36 (s, 3 H); MH + 354

[0314]

[0315] Step 2: N-Methyl-1-(1-tosyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine (28)

[0316] 1-Tosyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (100 mg, 1 eq) was dissolved in MeOH (1.41 mL, 0.2 M), and 2 M methylamine solution in MeOH (0.35 mL, 2.5 eq) was added. The mixture was stirred at room temperature for 1 h. After cooling to 0°C, NaBH4 (5.35 mg, 0.5 eq) was added and stirred at 0°C for 30 min. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain N-methyl-1-(1-tosyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine (98 mg of light brown sticky oil, yield 94%).

[0317] 1 H NMR (500 MHz, MeOH-d4) δ 8.08 (dd,J=8.02, 1.72 Hz, 1 H), 7.51 (d,J=8.02 Hz, 2 H), 7.47 (s, 1 H), 7.24 (br d,J=8.02 Hz, 2 H), 7.07 - 7.13 (m, 1 H), 6.93 - 6.98 (m, 1 H), 6.85 (dd,J=8.02, 1.15 Hz, 1 H), 4.97 (s, 2 H), 3.56 (s, 2 H), 2.37 (s, 3 H), 2.33 (s, 3 H); MH + 369

[0318]

[0319] Step 3: N-methyl-1-(1-tosyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine hydrochloride (29)

[0320] N-Methyl-1-(1-tosyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine (95 mg, 1 eq) was dissolved in ethyl acetate (2.58 mL, 0.1 M) and the mixture was cooled to 0°C. 1 M HCl in EtOAc (0.52 mL, 2.0 eq) was added at 0°C, the mixture was cooled to room temperature, and the mixture was stirred at room temperature for 30 min. The resulting solid was filtered with ethyl acetate to obtain N-methyl-1-(1-tosyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine hydrochloride (ivory solid, 91 mg, yield 87%).

[0321] 1 H NMR (500 MHz, MeOH-d4) δ 8.11 (dd,J=7.73, 1.43 Hz, 1 H), 7.75 (s, 1 H), 7.53 - 7.61 (m, 2 H), 7.27 (d,J=8.59 Hz, 2 H), 7.10 - 7.18 (m, 1 H), 6.98 (td,J=7.59, 1.43 Hz, 1 H), 6.88 (dd,J=8.02, 1.15 Hz, 1 H), 5.02 (s, 2 H), 4.06 (s, 2 H), 2.69 (s, 3 H), 2.34 (s, 3 H); MS m / z 369 (MH + - HCl)

[0322]

[0323] [Example 5] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine dihydrochloride (33)

[0324]

[0325] Step 1: 1-(Pyridin-3-ylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (31)

[0326] 60% sodium hydride (42 mg, 1.5 eq) in mineral oil was dissolved in DMF (1.75 mL, 0.4 M), then 1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (160 mg, 1 eq) dissolved in DMF (1.75 mL, 0.4 M) was slowly added, and the mixture was stirred at room temperature for 30 minutes. Pyridine-3-sulfonyl chloride (0.09 mL, 1.1 eq) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction was terminated by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(pyridin-3-ylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (brown solid, 189 mg, yield 79%).

[0327] 1 H NMR (500 MHz, MeOH-d4) δ 9.89 (s, 1 H), 8.95 (d,J=2.29 Hz, 1 H), 8.78 (dd,J=4.87, 1.43 Hz, 1 H), 8.43 (s, 1 H), 8.14 - 8.17 (m, 1 H), 8.09 (dd,J=8.02, 1.72 Hz, 1 H), 7.53 - 7.57 (m, 1 H), 7.15 - 7.19 (m, 1 H), 6.97 - 7.03 (m, 1 H), 6.88 (dd,J=8.31, 1.43 Hz, 1 H), 5.24 (s, 2H); MH + 341

[0328]

[0329] Step 2: N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine (32)

[0330] 1-(Pyridin-3-ylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (180 mg, 1 eq) was dissolved in MeOH (2.64 mL, 0.2 M), and a 2 M methylamine solution in MeOH (0.66 mL, 2.5 eq) was added. The mixture was stirred at room temperature for 40 minutes. After cooling to 0°C, NaBH4 (10 mg, 0.5 eq) was added and stirred at 0°C for 40 minutes. Afterwards, NaBH4 (10 mg, 0.5 eq) was additionally added and stirred at 0°C for 40 minutes. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine (122 mg of brown sticky oil, yield 65%).

[0331] 1 H NMR (500 MHz, MeOH-d4) δ 8.74 (d,J=1.72 Hz, 1 H), 8.71 (dd,J=4.87, 1.43 Hz, 1 H), 8.06 (dd,J=8.02, 1.72 Hz, 1 H), 7.99 (dt,J=7.73, 2.15 Hz, 1 H), 7.50 (s, 1 H), 7.45 - 7.49 (m, 1 H), 7.13 - 7.17 (m, 1 H), 7.01 (td,J=7.73, 1.15 Hz, 1 H), 6.88 (dd,J=8.02, 1.15 Hz, 1 H), 4.96 (s, 2 H), 3.57 (s, 2 H), 2.36 (s, 3 H); MH + 356

[0332]

[0333] Step 3: N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine dihydrochloride (33)

[0334] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine (120 mg, 1 eq) was dissolved in ethyl acetate (3.38 mL, 0.1 M) and cooled to 0°C. 1 M HCl in EtOAc (0.68 mL, 2.0 eq) was added at 0°C, cooled to room temperature, and stirred at room temperature for 30 min. The resulting solid was filtered with ethyl acetate and washed once more with acetonitrile to obtain N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine dihydrochloride (green solid, 98 mg, yield 74%).

[0335] 1 H NMR (500 MHz, MeOH-d4) δ 8.82 (d,J=2.29 Hz, 1 H), 8.75 (dd,J=5.15, 1.15 Hz, 1 H), 8.06 - 8.12 (m, 2 H), 7.83 (s, 1 H), 7.52 (dd,J=8.02, 5.15 Hz, 1 H), 7.19 (td,J=7.73, 1.15 Hz, 1 H), 7.01 - 7.06 (m, 1 H), 6.91 (d,J=8.59 Hz, 1 H), 5.03 (s, 2 H), 4.11 (s, 2 H), 2.73 (s, 3H); MS m / z 356 (MH + - 2HCl)

[0336]

[0337] [Example 6] 1-(1-Benzyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (39)

[0338]

[0339] Step 1: Methyl 1-benzyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxylate (35)

[0340] 60% sodium hydride (157 mg, 1.5 eq) in mineral oil was dissolved in DMF (6.54 mL, 0.4 M), then methyl 1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxylate (600 mg, 1 eq) dissolved in DMF (6.54 mL, 0.4 M) was slowly added, and the mixture was stirred at room temperature for 35 minutes. (Chloromethyl)benzene (0.34 mL, 1.1 eq) was slowly added, and the mixture was stirred at room temperature for 5 hours. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4, and then filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-benzyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxylate (594 mg of beige solid, yield 71%).

[0341] 1 H NMR (500 MHz, MeOH-d4) δ 7.50 (s, 1 H), 7.32 - 7.37 (m, 2 H), 7.25 - 7.29 (m, 1 H), 7.20 (dd,J=7.73, 1.43 Hz, 1 H), 7.10 (d,J=6.87 Hz, 2 H), 6.99 - 7.04 (m, 1 H), 6.87 (dd,J=8.02, 1.15 Hz, 1 H), 6.77 (td,J=7.45, 1.15 Hz, 1 H), 5.51 (s, 2 H), 5.40 (s, 2 H), 3.81 (s, 3 H); MH + 320

[0342]

[0343] Step 2: (1-Benzyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanol (36)

[0344] Methyl 1-benzyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxylate (270 mg, 1 eq) was dissolved in THF (4.23 mL, 0.2 M) and the temperature was lowered to 0℃. 1M DIBAL-H in toluene (2.54 mL, 3 eq) was slowly added and stirred at 0℃ for 30 minutes. The reaction was quenched by adding 1N HCl aqueous solution, diluted with ethyl acetate, and washed several times with distilled water and saturated aqueous potassium sodium tartrate solution. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1-benzyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanol. The synthesized compound was used in the following reaction without any separate purification process (274 mg of brown sticky oil, crude).

[0345] 1 H NMR (500 MHz, MeOH-d4) δ 7.28 - 7.33 (m, 2 H), 7.21 - 7.25 (m, 1 H), 7.13 (dd,J=7.73, 1.43 Hz, 1 H), 7.07 - 7.11 (m, 2 H), 6.93 - 6.98 (m, 1 H), 6.83 - 6.86 (m, 1 H), 6.83 (s, 1 H), 6.71 - 6.75 (m, 1 H), 5.41 (s, 2 H), 5.24 (s, 2 H), 4.50 (s, 2 H); MH + 292

[0346]

[0347] Step 3: 1-Benzyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (37)

[0348] (1-Benzyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanol (270 mg, 1 eq) was dissolved in MeCN (4.63 mL, 0.2 M), and molecular sieve 4Å (783 mg) was added and dried. N-Methylmorpholine N-oxide (152 mg, 1.5 eq) and TPAP (48.9 mg, 0.15 eq) were added and stirred at room temperature for 30 min. Celite ® The organic layer was filtered and washed with EtOAc, then distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, the residue was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-benzyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (red oil, 127 mg, two-step yield, 52%).

[0349] 1 H NMR (500 MHz, MeOH-d4) δ 9.72 (s, 1 H), 7.68 (s, 1 H), 7.33 - 7.38 (m, 2 H), 7.26 - 7.32 (m, 1 H), 7.23 (dd,J=8.02, 1.72 Hz, 1 H), 7.13 (d,J=7.45 Hz, 2 H), 7.05 (td,J=7.88, 1.43 Hz, 1 H), 6.88 (dd,J=8.02, 1.15 Hz, 1 H), 6.78 (td,J=7.59, 1.43 Hz, 1 H), 5.57 (s, 2 H), 5.43 (s, 2 H); MH + 290

[0350]

[0351] Step 4: 1-(1-Benzyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine (38)

[0352] 1-Benzyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carbaldehyde (125 mg, 1 eq) was dissolved in MeOH (2.16 mL, 0.2 M), and a 2 M methylamine solution in MeOH (0.54 mL, 2.5 eq) was added. The mixture was stirred at room temperature for 30 minutes. After cooling to 0°C, NaBH4 (8.2 mg, 0.5 eq) was added and stirred at room temperature for 20 minutes. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain 1-(1-benzyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine. The synthesized compound was used in the following reaction without a separate purification process (136 mg of yellow sticky oil, crude).

[0353] 1 H NMR (500 MHz, MeOH-d4) δ 7.28 - 7.33 (m, 2 H), 7.21 - 7.26 (m, 1 H), 7.15 (dd,J=7.73, 1.43 Hz, 1 H), 7.09 (d,J=6.87 Hz, 2 H), 6.95 - 6.99 (m, 1 H), 6.84 - 6.87 (m, 2 H), 6.73 - 6.77 (m, 1 H), 5.42 (s, 2 H), 5.20 (s, 2 H), 3.66 (s, 2 H), 2.45 (s, 3 H); MH + 305

[0354]

[0355] Step 5: 1-(1-Benzyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (39)

[0356] 1-(1-Benzyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine (130 mg, 1 eq) was dissolved in ethyl acetate (4.27 mL, 0.1 M) and cooled to 0°C. 1 M HCl in EtOAc (0.85 mL, 2.0 eq) was added at 0°C, warmed to room temperature, and stirred at room temperature for 30 min. The resulting solid was filtered with ethyl acetate to obtain 1-(1-benzyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (130 mg of ivory solid, 89% yield in two steps).

[0357] 1 H NMR (500 MHz, MeOH-d4) δ 7.30 - 7.35 (m, 2 H), 7.24 - 7.29 (m, 1 H), 7.21 (dd,J=7.73, 1.43 Hz, 1 H), 7.11 (d,J=6.87 Hz, 2 H), 7.06 (s, 1 H), 7.01 - 7.05 (m, 1 H), 6.90 (dd,J=8.02, 1.15 Hz, 1 H), 6.78 - 6.82 (m, 1 H), 5.48 (s, 2 H), 5.23 (s, 2 H), 4.08 (s, 2 H), 2.70 (s, 3) H); MS m / z 305 (MH + - HCl)

[0358]

[0359] [Example 7] 1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxamide (42)

[0360]

[0361] Step 1: 1,4-Dihydrochromeno[4,3-b]pyrrole-3-carboxylic acid (40)

[0362] Methyl 1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxylate (100 mg, 1 eq) was dissolved in MeOH (2.18 mL, 0.2 M), 50% NaOH in H2O was added, and the mixture was heated to 60°C. The mixture was stirred at 60°C for 5 hours and then cooled to 0°C. The reaction was quenched by adding 1 N HCl aqueous solution, acidified to pH 3, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain 1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxylic acid. The synthesized compound was used in the next reaction without any separate purification (brown solid 94 mg, crude).

[0363] 1 H NMR (500 MHz, MeOH-d4) δ 7.41 (s, 1 H), 7.30 (dd,J=7.45, 1.72 Hz, 1 H), 7.01 - 7.06 (m, 1 H), 6.86 - 6.90 (m, 1 H), 6.80 - 6.83 (m, 1 H), 5.49 (s, 2 H); MH + 216

[0364]

[0365] Step 2: N-Methyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxamide (41)

[0366] 1,4-Dihydrochromeno[4,3-b]pyrrole-3-carboxylic acid (90 mg, 1 eq), methylamine hydrochloride (42.4 mg, 1.5 eq), triethylamine (0.09 mL, 1.5 eq), and EDCI (0.09 mL, 1.2 eq) were dissolved in THF (0.84 mL, 0.5 M) and stirred at room temperature for 23 h. Afterwards, ethyl acetate was added to dilute the solution and washed with distilled water. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain N-methyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxamide (ivory solid, 59 mg, two-step yield, 59%).

[0367] 1 H NMR (500 MHz, MeOH-d4) δ 7.32 (s, 1 H), 7.29 (dd,J=7.45, 1.72 Hz, 1 H), 7.02 (td,J=7.73, 1.72 Hz, 1 H), 6.85 - 6.90 (m, 1 H), 6.81 (dd,J=8.02, 1.15 Hz, 1 H), 5.51 (s, 2 H), 2.84 (s, 3 H); MH + 229

[0368]

[0369] Step 3: 1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxamide (42)

[0370] 60% sodium hydride (20 mg, 2 eq) in mineral oil was dissolved in DMF (0.63 mL, 0.4 M), then N-methyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxamide (57 mg, 1 eq) dissolved in DMF (0.63 mL, 0.4 M) was slowly added and stirred at room temperature for 40 minutes. 3-Fluorobenzenesulfonyl chloride (0.04 mL, 1.5 eq) was added and stirred at room temperature for 30 minutes. The reaction was terminated by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography, and washed with diethyl ether to obtain 1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxamide (58 mg of white solid, yield 62%).

[0371] 1 H NMR (500 MHz, MeOH-d4) δ 8.06 (s, 1 H), 8.05 (dd,J=8.02, 1.72 Hz, 1 H), 7.50 - 7.56 (m, 2 H), 7.47 (dd,J=10.02, 1.43 Hz, 1 H), 7.37 - 7.44 (m, 1 H), 7.15 (td,J=7.73, 1.72 Hz, 1 H), 6.95 - 7.00 (m, 1 H), 6.87 (dd,J=8.02, 1.15 Hz, 1 H), 5.21 (s, 2 H), 2.86 (s, 3 H); MH + 387

[0372]

[0373] [Example 8] 1-(1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine hydrochloride (49)

[0374]

[0375] Step 1: Methyl 3-(((3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (44)

[0376] 3,4-Dihydronaphthalen-1(2H)-one oxime (1 g, 1 eq) was dissolved in DMSO (6.20 mL, 1 M), and TEA (0.87 mL, 1 eq) was slowly added at room temperature. Methyl propiolate (1.1 mL, 2 eq) dissolved in DMSO (2.48 mL, 2.5 M) was slowly added, and the temperature was increased to 70°C. After stirring at 70°C for 30 min, the temperature was lowered to room temperature. The reaction solution was diluted with DCM, washed several times with distilled water, and then with brine. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 3-(((3,4-dihydronaphthalene-1(2H)-ylidene)amino)oxy)acrylate (yellow oil 1.5 g, yield 98%, 4.2:1 mixture of (E / Z) isomer).

[0377] 1 H NMR (500 MHz, DMSO-d6) for the major (E)-isomer δ 8.03 (d,J=12.60 Hz, 1 H), 7.96 (dd,J=8.31, 1.43 Hz, 1 H), 7.36 - 7.43 (m, 1 H), 7.24 - 7.31 (m, 2 H), 5.70 (d,J=12.60 Hz, 1 H), 3.65 (s, 3 H), 2.84 (t,J=6.59 Hz, 2 H), 2.73 - 2.80 (m, 2 H), 1.77 - 1.86 (m, 2 H), Partial 1 H NMR for the minor (Z)-isomer δ 7.89 (d,J=8.02 Hz, 1 H), 7.60 (d,J=7.45 Hz, 1 H), 4.97 (d,J=7.45 Hz, 1 H), 3.62 (s, 3 H), 2.91 (t,J=6.59 Hz, 2 H); MH + 246

[0378]

[0379] Step 2: Methyl 4,5-dihydro-1H-benzo[g]indole-3-carboxylate (45)

[0380] Methyl 3-(((3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (500 mg, 1 eq) was dissolved in 1,4-dioxane (13.59 mL, 0.15 M), DBU (0.3 mL, 1 eq) was added, and the mixture was heated in a microwave at 150°C for 30 min. After that, the mixture was further heated in a microwave at 150°C for 20 min. The reaction solution was diluted with ethyl acetate, washed several times with distilled water, and then washed with brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 4,5-dihydro-1H-benzo[g]indole-3-carboxylate (brown solid, 275 mg, yield 60%).

[0381] 1 H NMR (500 MHz, DMSO-d6) δ 11.95 (br s, 1 H), 7.44 - 7.51 (m, 2 H), 7.16 - 7.24 (m, 2 H), 7.03 - 7.10 (m, 1 H), 3.72 (s, 3 H), 2.82 - 2.93 (m, 4 H); MH + 228

[0382]

[0383] Step 3: Methyl 1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (46)

[0384] Methyl 4,5-dihydro-1H-benzo[g]indole-3-carboxylate (260 mg, 1 eq) and DMAP (140 mg, 1.0 eq) were dissolved in MeCN (1.53 mL, 0.75 M), 3-fluorobenzenesulfonyl chloride (0.17 mL, 1.1 eq) and DIPEA (0.80 mL, 4 eq) were added, and the mixture was stirred at room temperature for 23 h. The mixture was diluted with ethyl acetate and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (orange oil 390 mg, yield 85%).

[0385] 1 H NMR (500 MHz, MeOH-d4) δ 8.02 (s, 1 H), 7.93 (d,J=8.02 Hz, 1 H), 7.47 - 7.52 (m, 1 H), 7.43 - 7.46 (m, 1 H), 7.35 - 7.41 (m, 2 H), 7.14 - 7.27 (m, 3 H), 3.84 (s, 3 H), 2.74 - 2.79 (m, 2 H), 2.58 - 2.64 (m, 2 H); MH + 386

[0386]

[0387] Step 4: (1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (47)

[0388] Methyl 1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (380 mg, 1 eq) was dissolved in THF (4.93 mL, 0.2 M) and the temperature was lowered to 0℃. 1M DIBAL-H in toluene (2.96 mL, 3 eq) was added and stirred at 0℃ for 40 minutes. The reaction was quenched by adding 1N HCl aqueous solution, diluted with ethyl acetate, and washed several times with distilled water and saturated aqueous potassium sodium tartrate solution. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol. The synthesized compound was used in the following reaction without a separate purification process (370 mg of brown sticky oil, crude).

[0389] 1 H NMR (500 MHz, MeOH-d4) δ 7.90 (d,J=8.59 Hz, 1 H), 7.40 - 7.46 (m, 1 H), 7.32 - 7.38 (m, 2 H), 7.31 (s, 1 H), 7.22 - 7.27 (m, 2 H), 7.18 - 7.22 (m, 1 H), 7.12 - 7.17 (m, 1 H), 4.43 (s, 2 H), 2.56 - 2.63 (m, 2 H), 2.41 - 2.47 (m, 2 H); MH + 358

[0390]

[0391] Step 5: 1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (48)

[0392] (1-((3-Fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (360 mg, 1 eq) was dissolved in DCM (3.88 mL, 0.26 M), TEMPO (47.2 mg, 0.3 eq) and PhI(OAc)2 (519 mg, 1.6 eq) were added, and the mixture was stirred at room temperature for 1 hour and 20 minutes. The reaction was terminated by adding saturated aqueous NaHCO3 solution, diluted with DCM, and washed with distilled water and brine. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (orange-brown solid, 243 mg, two-step yield 67%).

[0393] 1 H NMR (500 MHz, MeOH-d4) δ 9.91 (s, 1 H), 8.27 (s, 1 H), 7.96 (d,J=7.45 Hz, 1 H), 7.48 - 7.53 (m, 2 H), 7.38 - 7.46 (m, 2 H), 7.17 - 7.27 (m, 3 H), 2.77 - 2.83 (m, 2 H), 2.59 - 2.64 (m, 2 H); MH + 356

[0394]

[0395] Step 6: 1-(1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine hydrochloride (49)

[0396] 1-((3-Fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (235 mg, 1 eq) was dissolved in MeOH (3.31 mL, 0.2 M), and 2 M methylamine solution in MeOH (0.83 mL, 2.5 eq) was added. The mixture was stirred at room temperature for 1 hour and 30 minutes. After lowering the temperature to 0°C, NaBH4 (12.5 mg, 0.5 eq) was added and stirred at 0°C for 40 minutes. The reaction was terminated by adding 1 N HCl aqueous solution, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography, and washed once more with EtOAc to obtain 1-(1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine hydrochloride (white solid 174 mg, yield 64%).

[0397] 1 H NMR (500 MHz, MeOH-d4) δ 7.95 (d,J=8.02 Hz, 1 H), 7.63 (s, 1 H), 7.44 - 7.50 (m, 1 H), 7.40 - 7.43 (m, 1 H), 7.35 - 7.40 (m, 1 H), 7.32 (dt,J=8.16, 2.22 Hz, 1 H), 7.22 - 7.28 (m, 2 H), 7.16 - 7.21 (m, 1 H), 4.05 (s, 2 H), 2.66 (s, 3 H), 2.61 - 2.65 (m, 2 H), 2.47 - 2.53 (m, 2H); MS m / z 371 (MH + - HCl)

[0398]

[0399] [Example 9] 1-((3-fluorophenyl)sulfonyl)-3-(methoxymethyl)-4,5-dihydro-1H-benzo[g]indole (52)

[0400]

[0401] Step 1: Methyl 1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (46)

[0402] Methyl 4,5-dihydro-1H-benzo[g]indole-3-carboxylate (200 mg), DMAP (215 mg, 2.0 eq) were dissolved in MeCN (1.06 mL), and 3-fluorobenzenesulfonyl chloride (140 μL, 1.2 eq) and DIPEA (770 μL, 5.0 eq) were added dropwise, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed several times with distilled water and brine. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal phase silica gel column chromatography to obtain methyl 1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (red oil 293 mg, yield 86%). MH + 386

[0403]

[0404] Step 2: (1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (47)

[0405] Methyl 1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (195 mg) was dissolved in THF (2.53 mL) and cooled to 0°C. 1 M DIBAL-H (1.52 mL, 3.0 eq) was added dropwise to the reaction mixture and stirred at room temperature for 1 h. After quenching the reaction with 1 N HCl, the mixture was diluted with ethyl acetate and washed several times with distilled water. The extracted organic layer was separated into Na2SO4 4- cast After drying using ethanol, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol. The synthesized compound was used in the following reaction without purification (colorless oil, crude). MH + 358

[0406]

[0407] Step 3: 1-((3-fluorophenyl)sulfonyl)-3-(methoxymethyl)-4,5-dihydro-1H-benzo[g]indole (52)

[0408] (1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (100 mg) was dissolved in methanol (1.40 mL), and sulfuric acid (120 μL, 8.0 eq) was slowly added dropwise, and stirred at 40°C for 16 hours. The reaction mixture was diluted with ethyl acetate, and then NaHCO3 was added. After adjusting the pH to 7-8 using distilled water, the extracted organic layer was washed several times with Na2SO4. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain 1-((3-fluorophenyl)sulfonyl)-3-(methoxymethyl)-4,5-dihydro-1H-benzo[g]indole (60 mg of red oil, yield 78%).

[0409] 1 H NMR (500 MHz, MeOH-d4) δ 7.89 (d,J=6.87 Hz, 1 H), 7.41 - 7.47 (m, 1 H), 7.31 - 7.38 (m, 3 H), 7.19 - 7.27 (m, 3 H), 7.13 - 7.17 (m, 1 H), 4.29 (d,J=1.15 Hz, 2 H), 3.23 (s, 3 H), 2.56 - 2.63 (m, 2 H), 2.40 - 2.46 (m, 2 H); MH + 372

[0410]

[0411] [Example 10] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanamine dihydrochloride (57)

[0412]

[0413] Step 1: Methyl 1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (53)

[0414] Methyl 4,5-dihydro-1H-benzo[g]indole-3-carboxylate (450 mg) was added dropwise to a solution of sodium hydride (158 mg, 2.0 eq) in DMF (2.64 mL), and the mixture was stirred at room temperature for 30 minutes. Pyridine-3-sulfonyl chloride (280 μL, 1.2 eq) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After quenching the reaction by adding H2O, the mixture was diluted with ethyl acetate, and then washed several times with distilled water. The extracted organic layer was treated with Na2SO4. After drying using ethanol, the residue was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain methyl 1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (brown oil, 574 mg, yield 74%). MH + 369

[0415]

[0416] Step 2: (1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (54)

[0417] Methyl 1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (574 mg) was dissolved in THF (7.79 mL) and cooled to 0°C. 1M DIBAL-H (4.67 mL, 3.0 eq) was added dropwise to the reaction mixture and stirred at room temperature for 1 hour. After quenching the reaction with 1 N HCl, the mixture was diluted with ethyl acetate and washed several times with distilled water. The extracted organic layer was treated with Na2SO4. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain (1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (brown oil 320 mg, yield 60%). MH + 341

[0418]

[0419] Step 3: 1-(Pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (55)

[0420] (1-(Pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (300 mg), TEMPO (41.31 mg, 0.3 eq), PhI(OAc)2 (454 mg, 1.6 eq) were dissolved in CH2Cl2 (4.41 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and then distilled water and NaHCO3(aq) were added. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain 1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (brown oil, 128 mg, yield 43%). MH + 339

[0421]

[0422] Step 4: N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanamine (56)

[0423] 2 M methylamine (370 μL, 2.5 eq) was added dropwise to a solution of 1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (100 mg) in methanol (1.48 mL), and the mixture was stirred at room temperature for 1 hour. After lowering the reaction mixture to 0°C, NaBH4 (5.59 mg, 0.5 eq) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain N-methyl-1-(1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanamine (yellow oil 55 mg, yield 52%). MH + 354

[0424]

[0425] Step 5: N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanamine dihydrochloride (57)

[0426] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanamine (44 mg) was dissolved in ethyl acetate (1.24 mL) and the mixture was cooled to 0°C. 1 M HCl in EtOAc (250 μL, 2.0 eq) was added dropwise to the reaction mixture, which was stirred at room temperature for 1 h. The mixture was filtered under reduced pressure to obtain N-methyl-1-(1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanamine dihydrochloride (brown solid, 32 mg, yield 72%).

[0427] 1H NMR (500 MHz, DMSO-d6) δ 8.84 (br d,J=5.15 Hz, 1 H), 8.81 (br d,J=3.44 Hz, 1 H), 8.74 (s, 1 H), 7.99 (dd,J=8.31, 1.43 Hz, 1 H), 7.76 (d,J=8.02 Hz, 1 H), 7.71 (s, 1 H), 7.58 (dd,J=8.02, 5.15 Hz, 1 H), 7.24 - 7.31 (m, 2 H), 7.16 - 7.23 (m, 1 H), 3.98 (br t,J=5.44 Hz, 1 H), 2.55 - 2.62 (m, 2 H), 2.51 - 2.52 (m, 3 H), 2.48 (br s, 2 H); MS m / z 354 (MH + - 2HCl)

[0428]

[0429] [Example 11] 1-(7-ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine hydrochloride (68)

[0430]

[0431] Step 1: 6-Ethyl-3,4-dihydronaphthalen-1(2H)-one (60)

[0432] 6-Bromo-3,4-dihydronaphthalen-1(2H)-one (2 g, 1 eq), ethylboronic acid (985 mg, 1.5 eq), palladium (II) acetate (100 mg, 0.05 eq), triphenylphosphine (233 mg, 0.1 eq), and potassium phosphate (7.54 g, 4 eq) were dissolved in THF (44.4 mL, 0.2 M), the temperature was increased to 75°C, and the mixture was stirred for 4 hours and 30 minutes. After lowering the temperature to room temperature, ethyl acetate was added to the reaction solution, diluted, and washed several times with distilled water and then brine. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 6-ethyl-3,4-dihydronaphthalen-1(2H)-one (purple liquid 1.1 g, yield 71%).

[0433] 1 H NMR (500 MHz, MeOH-d4) δ 7.85 - 7.90 (m, 1 H), 7.13 - 7.20 (m, 2 H), 2.97 (t,J=6.11 Hz, 2 H), 2.68 (q,J=7.64 Hz, 2 H), 2.62 (dd,J=7.11, 6.04 Hz, 2 H), 2.08 - 2.16 (m, 2 H), 1.25 (t,J=7.64 Hz, 3 H); MH + 175

[0434]

[0435] Step 2: 6-Ethyl-3,4-dihydronaphthalen-1(2H)-one oxime (61)

[0436] 6-Ethyl-3,4-dihydronaphthalen-1(2H)-one (1.1 g, 1 eq), hydroxylamine HCl (483 mg, 1.1 eq), and sodium acetate (777 mg, 1.5 eq) were dissolved in ethanol / H2O (1:1, 38 mL, 0.17 M), heated to 90°C, and stirred for 2 hours. After lowering the temperature to room temperature, ethyl acetate was added to the reaction solution, diluted, and washed several times with distilled water and then brine. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain 6-ethyl-3,4-dihydronaphthalen-1(2H)-one oxime. The synthesized compound was used in the next reaction without any separate purification (beige sticky solid 1.32 g, crude).

[0437] 1 H NMR (500 MHz, MeOH-d4) δ 7.78 (d,J=7.95 Hz, 1 H), 6.99 - 7.02 (m, 1 H), 6.98 (s, 1 H), 2.69 - 2.78 (m, 4 H), 2.60 (q,J=7.64 Hz, 2 H), 1.78 - 1.86 (m, 2 H), 1.21 (t,J=7.64 Hz, 3 H); MH + 190

[0438]

[0439] Step 3: Methyl 3-(((6-ethyl-3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (62)

[0440] 6-Ethyl-3,4-dihydronaphthalen-1(2H)-one oxime (1.19 g, 1 eq) was dissolved in DMSO (6.31 mL, 1 M), and TEA (0.88 mL, 1 eq) was slowly added at 70°C. Methyl propiolate (1.12 mL, 2 eq) dissolved in DMSO (2.52 mL, 2.5 M) was slowly added, and the mixture was stirred at room temperature for 20 min. The reaction solution was diluted with EtOAc, washed several times with distilled water, and then washed with brine. The extracted organic layer was dried over Na2SO4, and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 3-(((6-ethyl-3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (1.51 g of yellow sticky oil, yield 87%, 12.5:1 mixture of (E / Z) isomer).

[0441] 1 H NMR (500 MHz, DMSO-d6) for the major (E)-isomer δ 8.06 (d,J=12.53 Hz, 1 H), 7.91 (d,J=8.10 Hz, 1 H), 7.10 (dd,J=8.33, 1.60 Hz, 1 H), 7.07 (s, 1 H), 5.65 (d,J=12.38 Hz, 1 H), 3.72 (s, 3 H), 2.86 (t,J=6.65 Hz, 2 H), 2.75 - 2.79 (m, 2 H), 2.64 (q,J=7.54 Hz, 2 H), 1.83 - 1.92 (m, 2 H), 1.23 (t,J=7.57 Hz, 3 H), Partial 1 H NMR for the minor (Z)-isomer δ 8.01 (d,J=8.10 Hz, 1 H), 7.88 (d,J=8.71 Hz, 1 H), 7.55 (d,J=7.49 Hz, 1 H), 4.93 (d,J=7.49 Hz, 1 H), 3.71 (s, 1 H); MH + 274

[0442]

[0443] Step 4: Methyl 7-ethyl-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (63)

[0444] Methyl 3-(((6-ethyl-3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (1.5 g, 1 eq) was dissolved in 1,4-dioxane (52.2 mL, 0.1 M), DBU (3.12 mL, 4 eq) was added, and the temperature was raised to 110°C. After heating at 110°C for 15 h, the temperature was lowered to room temperature. The reaction solution was diluted with ethyl acetate, washed several times with distilled water, and then washed with brine. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 7-ethyl-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (ivory solid, 968 mg, yield 69%).

[0445] 1 H NMR (500 MHz, MeOH-d4) δ 7.36 (s, 1 H), 7.25 (d,J=7.79 Hz, 1 H), 7.04 (s, 1 H), 7.01 (dd,J=7.72, 1.76 Hz, 1 H), 3.79 (s, 3 H), 2.91 - 2.95 (m, 2 H), 2.85 - 2.90 (m, 2 H), 2.59 (q,J=7.54 Hz, 2 H), 1.22 (t,J=7.64 Hz, 3 H); MH + 256

[0446]

[0447] Step 5: Methyl 7-ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (64)

[0448] 60% sodium hydride (96 mg, 1.5 eq) in mineral oil was dissolved in THF (4.01 mL, 0.4 M), then methyl 7-ethyl-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (410 mg, 1 eq) dissolved in THF (4.01 mL, 0.4 M) was slowly added, and the mixture was stirred at room temperature for 50 minutes. 3-Fluorobenzenesulfonyl chloride (0.23 mL, 1.1 eq) was added, and the mixture was stirred at room temperature for 22 hours. The reaction was terminated by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 7-ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (440 mg of brown sticky oil, yield 66%).

[0449] 1 H NMR (500 MHz, MeOH-d4) δ 7.99 (s, 1 H), 7.85 (d,J=8.10 Hz, 1 H), 7.47 - 7.52 (m, 1 H), 7.43 - 7.46 (m, 1 H), 7.35 - 7.41 (m, 2 H), 7.09 (dd,J=7.95, 1.83 Hz, 1 H), 7.06 (s, 1 H), 3.83 (s, 3 H), 2.73 - 2.78 (m, 2 H), 2.61 (dq,J=14.60, 7.36 Hz, 4 H), 1.23 (t,J=7.64 Hz, 3 H); MH + 414

[0450]

[0451] Step 6: (7-Ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (65)

[0452] Methyl 7-ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (406 mg, 1 eq) was dissolved in THF (4.91 mL, 0.2 M) and the temperature was lowered to 0°C. 1M DIBAL-H in toluene (2.95 mL, 3 eq) was added and stirred at 0°C for 2 hours. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water and a saturated aqueous solution of potassium sodium tartrate. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (7-ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol. The synthesized compound was used in the next reaction without a separate purification process (purple sticky oil 392 mg, crude).

[0453] 1 H NMR (500 MHz, MeOH-d4) δ 7.81 (d,J=7.95 Hz, 1 H), 7.40 - 7.46 (m, 1 H), 7.30 - 7.38 (m, 2 H), 7.28 (t,J=0.92 Hz, 1 H), 7.25 (dt,J=8.25, 2.06 Hz, 1 H), 7.08 (dd,J=8.02, 1.91 Hz, 1 H), 7.05 (s, 1 H), 4.42 (d,J=0.92 Hz, 2 H), 2.63 (q,J=7.64 Hz, 2 H), 2.55 - 2.60 (m, 2 H), 2.41 - 2.45 (m, 2 H), 1.24 (t,J=7.64 Hz, 3 H); MH + 386

[0454]

[0455] Step 7: 7-Ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (66)

[0456] (7-Ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (378 mg, 1 eq) was dissolved in MeCN (4.9 mL, 0.2 M), and molecular sieve 4Å (1.10 g) was added and dried. N-Methylmorpholine N-oxide (161 mg, 1.5 eq) and TPAP (52 mg, 0.15 eq) were added and stirred at room temperature for 1 h. The molecular sieve 4Å was removed by filtration, washed with EtOAc, and then with distilled water. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 7-ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (brown sticky solid, 253 mg, two-step yield, 67%).

[0457] 1 H NMR (500 MHz, MeOH-d4) δ 9.89 (s, 1 H), 8.23 ​​(s, 1 H), 7.87 (d,J=8.10 Hz, 1 H), 7.48 - 7.54 (m, 2 H), 7.38 - 7.46 (m, 2 H), 7.09 (dd,J=8.10, 1.83 Hz, 1 H), 7.06 (s, 1 H), 2.76 - 2.81 (m, 2 H), 2.57 - 2.65 (m, 4 H), 1.23 (t,J=7.57 Hz, 3 H); MH + 384

[0458]

[0459] Step 8: 1-(7-Ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (67)

[0460] 7-Ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (250 mg, 1 eq) was dissolved in MeOH (3.26 mL, 0.2 M), and 2 M methylamine solution in MeOH (0.81 mL, 2.5 eq) was added and stirred at room temperature for 4 h. After lowering the temperature to 0°C, NaBH4 (12.3 mg, 0.5 eq) was added and stirred at room temperature for 20 min. The reaction was terminated by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by amine column chromatography to obtain 1-(7-ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (pale yellow oil, 194 mg, yield 74%).

[0461] 1 H NMR (500 MHz, MeOH-d4) δ 7.81 (d,J=7.95 Hz, 1 H), 7.40 - 7.46 (m, 1 H), 7.35 - 7.38 (m, 1 H), 7.31 - 7.35 (m, 1 H), 7.30 (s, 1 H), 7.27 (dt,J=8.25, 2.06 Hz, 1 H), 7.09 (dd,J=8.02, 1.91 Hz, 1 H), 7.06 (s, 1 H), 3.54 (d,J=0.76 Hz, 2 H), 2.63 (q,J=7.54 Hz, 2 H), 2.55 - 2.60 (m, 2 H), 2.38 - 2.43 (m, 2 H), 2.32 (s, 3 H), 1.25 (t,J=7.64 Hz, 3 H); MH + 399

[0462]

[0463] Step 9: 1-(7-ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine hydrochloride (68)

[0464] 1-(7-Ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (180 mg, 1 eq) was dissolved in ethyl acetate (2.26 mL, 0.2 M), 1N HCl in EtOAc (0.50 mL, 1.1 eq) was added, and the mixture was stirred at room temperature for 1 h. The resulting solid was filtered with ethyl acetate to obtain 1-(7-ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine hydrochloride (white solid 162 mg, yield 82%).

[0465] 1 H NMR (500 MHz, MeOH-d4) δ 7.87 (d,J=8.10 Hz, 1 H), 7.62 (s, 1 H), 7.45 - 7.50 (m, 1 H), 7.41 - 7.44 (m, 1 H), 7.35 - 7.40 (m, 1 H), 7.33 (dt,J=8.21, 2.01 Hz, 1 H), 7.09 - 7.12 (m, 1 H), 7.09 (s, 1 H), 4.08 (s, 2 H), 2.68 (s, 3 H), 2.59 - 2.66 (m, 4 H), 2.47 - 2.52 (m, 2) H), 1.24 (t,J=7.64 Hz, 3 H); MS m / z 399 (MH + - HCl)

[0466]

[0467] [Example 12] 1-(1-((3-fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (76)

[0468]

[0469] Step 1: (E)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (70)

[0470] 6-Methoxy-3,4-dihydronaphthalen-1(2H)-one (1.5 g), hydroxylamine hydrochloride (651 mg, 1.1 eq), and sodium acetate (1.05 g, 1.5 eq) were dissolved in ethanol (21 mL) / H2O (21 mL) and stirred at 80°C for 16 h. The reaction mixture was diluted with ethyl acetate and washed several times with distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (E)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime. The synthesized compound was used in the following reaction without purification (1.644 g of light brown solid, crude).

[0471] 1 H NMR (500 MHz, MeOH-d4) δ 7.79 (d,J=8.71 Hz, 1 H) 6.73 (dd,J=8.71, 2.75 Hz, 1 H) 6.69 (d,J=2.60 Hz, 1 H) 4.87 (s, 3 H) 2.72 (q,J=7.03 Hz, 4 H) 1.82 (dd,J=6.80, 5.88 Hz, 2 H); MH + 192

[0472]

[0473] Step 2: Methyl 3-((((E)-6-methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (71)

[0474] Triethylamine (1.18 mL, 1.0 eq) was slowly added dropwise to a solution of (E)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (1.64 g) in DMSO (8.51 mL). A solution of methyl propiolate (1.51 mL, 2.0 eq) in DMSO (3.4 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 40 minutes. CH2Cl2 was added to the reaction mixture. After diluting, the solution was washed several times with distilled water and brine. The extracted organic layer was washed with Na2SO4. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain methyl 3-((((E)-6-methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (ivory oil 2.12 g, yield 90%). MH + 276

[0475]

[0476] Step 3: Methyl 7-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (72)

[0477] 1,8-diazabicyclo[5,4,0]undec-7-ene (5.08 mL, 4.0 eq) was added to a solution of methyl 3-((((E)-6-methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (2.12 g) in 1,4-dioxane (85 mL), and the mixture was stirred at 110°C for 16 h. The reaction mixture was diluted with ethyl acetate and washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain methyl 7-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (pink solid 1.25 g, yield 57%).

[0478] 1 H NMR (500 MHz, DMSO-d6) δ 11.81 (br s, 1 H), 7.31 - 7.47 (m, 2 H), 6.83 (d,J=2.60 Hz, 1 H), 6.78 (dd,J=8.41, 2.75 Hz, 1 H), 3.74 (s, 3 H), 3.70 (s, 3 H), 2.80 - 2.89 (m, 4 H); MH + 258

[0479]

[0480] Step 4: Methyl 1-((3-fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (73)

[0481] Methyl 7-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (500 mg) was added to a solution of sodium hydride (117 mg, 1.5 eq) in N,N-dimethylformamide (9.72 mL), and the mixture was stirred for 30 minutes. 3-Fluorobenzenesulfonyl chloride (284 μL, 1.1 eq) was added to the reaction solution, and the mixture was stirred at room temperature for 20 minutes. After terminating the reaction by adding H2O, the mixture was diluted with ethyl acetate, and then washed several times with distilled water. The extracted organic layer was treated with Na2SO4. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain methyl 1-((3-fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (yellow oil 670 mg, yield 87%).

[0482] 1 H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1 H) 7.60 - 7.71 (m, 4 H) 7.56 (dt,J=7.45, 1.62 Hz, 1 H) 6.87 (d,J=2.75 Hz, 1 H) 6.82 (dd,J=8.71, 2.75 Hz, 1 H) 3.78 (s, 3 H) 3.75 (s, 3 H) 2.68 - 2.76 (m, 2 H) 2.59 - 2.65 (m, 2 H); MH + 416

[0483]

[0484] Step 5: (1-((3-fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (74)

[0485] Methyl 1-((3-fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (670 mg) was dissolved in THF (8.06 mL) and the solution was cooled to 0°C. 1 M-DIBAL (4.84 mL, 3.0 eq) in toluene was added and stirred at 0°C for 40 minutes. After terminating the reaction by adding H2O, the mixture was diluted with ethyl acetate and washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1-((3-fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol. The synthesized compound was used in the following reaction without purification (green oil 703 mg, crude).

[0486] 1 H NMR (500 MHz, DMSO-d6) δ 7.67 (d,J=8.71 Hz, 1 H), 7.52 - 7.62 (m, 2 H), 7.33 - 7.38 (m, 2 H), 7.21 (s, 1 H), 6.86 (d,J=2.60 Hz, 1 H), 6.83 (dd,J=8.71, 2.75 Hz, 1 H), 4.95 (t,J=5.27 Hz, 1 H), 4.29 (d,J=4.58 Hz, 2 H), 3.76 (s, 3 H), 2.53 - 2.58 (m, 2 H), 2.35 - 2.42 (m, 2H); MH + 388

[0487]

[0488] Step 6: 1-((3-fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (75)

[0489] (1-((3-fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (620 mg) was dissolved in MeCN (8.10 mL), and molecular sieve 4Å (1.86 g), NMO (438 mg, 2.31 eq), and TPAP (85.4 mg, 0.15 eq) were added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was filtered through celite ® After filtration, the filtrate was diluted with ethyl acetate and washed several times with distilled water. The extracted organic layer was dried with Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal pressure silica gel column chromatography to obtain 1-((3-fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (brown oil 395 mg, yield 63%).

[0490] 1 H NMR (500 MHz, DMSO-d6) δ 9.95 (d,J=0.76 Hz, 1 H), 8.46 (s, 1 H), 8.08 (d,J=7.79 Hz, 1 H), 7.87 (d,J=8.10 Hz, 1 H), 7.77 (t,J=7.87 Hz, 1 H), 7.53 - 7.57 (m, 1 H), 7.35 - 7.40 (m, 1 H), 7.30 - 7.35 (m, 2 H), 7.19 (d,J=7.34 Hz, 1 H), 2.96 - 3.22 (m, 1 H), 2.08 - 2.31 (m, 1) H), 1.58 - 1.96 (m, 3 H); MH + 386

[0491]

[0492] Step 7: 1-(1-((3-fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (76)

[0493] 1-((3-Fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (386 mg) was dissolved in methanol (5.01 mL), 2M methylamine in MeOH (0.75 mL, 1.5 eq) was added, and the mixture was stirred at room temperature for 1 hour. After lowering the reaction solution to 0°C, NaBH4 (18.9 mg, 0.5 eq) was added, and the mixture was stirred at room temperature for 30 minutes. After quenching the reaction by adding H2O, the mixture was diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried with Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain 1-(1-((3-fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (brown oil, 310 mg, yield 77%).

[0494] 1 H NMR (500 MHz, DMSO-d6) δ 7.66 (d,J=8.56 Hz, 1 H), 7.51 - 7.60 (m, 2 H), 7.31 - 7.37 (m, 2 H), 7.21 (s, 1 H), 6.80 - 6.89 (m, 2 H), 3.77 (s, 3 H), 3.43 (s, 2 H), 2.52 - 2.58 (m, 2 H), 2.34 - 2.41 (m, 2 H), 2.15 (s, 3 H); MH + 401

[0495]

[0496] [Example 13] 1-((3-fluorophenyl)sulfonyl)-3-((methylamino)methyl)-4,5-dihydro-1H-benzo[g]indole-7-ol (77)

[0497]

[0498] 1-(1-((3-Fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (179 mg) was dissolved in CH2Cl2 (2.23 mL) and then cooled to 0°C. 1 M BBr3 in CH2Cl2 (670 μL, 1.5 eq) was slowly added to the reaction solution and stirred at room temperature for 4 hours. 1 M NaOH was added to the reaction solution to make it alkaline, and then CH2Cl2 was added. After diluting, the solution was washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by amino silica gel column chromatography to obtain 1-((3-fluorophenyl)sulfonyl)-3-((methylamino)methyl)-4,5-dihydro-1H-benzo[g]indol-7-ol (pale red solid, 71 mg, yield 41%).

[0499] 1 H NMR (500 MHz, DMSO-d6) δ 9.39 - 9.56 (m, 1 H), 7.50 - 7.60 (m, 3 H), 7.28 - 7.37 (m, 2 H), 7.14 (s, 1 H), 6.60 - 6.71 (m, 2 H), 3.38 (s, 2 H), 2.46 (br d,J=7.79 Hz, 2 H), 2.34 (br d,J=7.64 Hz, 2 H), 2.12 (s, 3 H); MH + 387

[0500]

[0501] [Example 14] 1-(1-((3-fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (85)

[0502]

[0503] Step 1: (E)-7-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (79)

[0504] 7-Methoxy-3,4-dihydronaphthalen-1(2H)-one (1 g, 1 eq, 5.68 mmol) was dissolved in EtOH / H2O (33 mL / 33 mL, 0.2 M), and hydroxylamine hydrochloride (433.8 mg, 1.1 eq, 6.24 mmol) and sodium acetate (698.3 mg, 1.5 eq, 8.51 mmol) were added. The mixture was stirred at 90°C for 4 h. After the reaction was completed, the temperature was lowered to room temperature and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain (E)-7-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (brown solid, 1.2 g, 111%).

[0505] 1 H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1 H), 7.32 - 7.38 (m, 1 H), 7.10 (d,J=8.41 Hz, 1 H), 6.80 - 6.89 (m, 1 H), 3.72 (s, 3 H), 2.54 - 2.68 (m, 4 H), 1.72 (quin,J=6.34 Hz, 2 H); MH + 192

[0506]

[0507] Step 2: Methyl 3-((((E)-7-methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (80)

[0508] The concentrated residue of (E)-7-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (1.2 g, 1 eq, 5.68 mmol) was dissolved in DMSO (2.5 mL, 2.3 M) and stirred at room temperature, after which triethylamine (786.7 μL, 1 eq, 5.68 mmol) was added. Methyl propiolate (1004.4 μL, 2 eq, 11.4 mmol) was dissolved in DMSO (1.3 mL, 4.4 M) and added to the reaction solution, and stirred at 70°C for 15 minutes. After completion of the reaction, H2O was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed once with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by normal silica gel column chromatography (10-20% EtOAc / Hex) to obtain methyl 3-((((E)-7-methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (clear gel, 1.06 g, yield 68%).

[0509] 1 H NMR (500 MHz, DMSO-d6) δ 8.05 (d,J=12.53 Hz, 1 H), 7.43 (d,J=2.75 Hz, 1 H), 7.20 (d,J=8.56 Hz, 1 H), 7.01 (dd,J=8.41, 2.75 Hz, 1 H), 5.69 (d,J=12.53 Hz, 1 H), 3.77 (s, 3 H), 3.65 (s, 3 H), 2.81 (t,J=6.57 Hz, 2 H), 2.69 (t,J=6.04 Hz, 2 H), 1.69 - 1.83 (m, 2 H); MH + 276

[0510]

[0511] Step 3: Methyl 8-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (81)

[0512] Methyl 3-((((E)-7-methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (1.06 g, 1 eq, 3.85 mmol) was dissolved in 1,4-dioxane (38.5 mL, 0.1 M), 1,8-diazabicyclo[5.4.0]undec-7-ene (2.3 mL, 4 eq, 15.4 mmol) was added, and the mixture was stirred at 110°C for 19 hours. After the reaction was completed, the temperature was lowered to room temperature, H2O was added to terminate the reaction, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was recrystallized from EtOAc / Hex and filtered to obtain methyl 8-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate as a filter cake (687 mg of brown solid, yield 69%).

[0513] 1 H NMR (500 MHz, DMSO-d6) δ 11.93 (br s, 1 H), 7.47 (d,J=2.90 Hz, 1 H), 7.14 (d,J=2.75 Hz, 1 H), 7.10 (d,J=8.10 Hz, 1 H), 6.63 (dd,J=8.18, 2.67 Hz, 1 H), 3.74 (s, 3 H), 3.70 (s, 3 H), 2.81 - 2.89 (m, 2 H), 2.74 - 2.81 (m, 2 H); MH + 258

[0514]

[0515] Step 4: Methyl 1-((3-fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (82)

[0516] Sodium hydride (160.2 mg, 1.5 eq, 4.01 mmol) was dissolved in THF (6.7 mL, 0.2 M) and stirred, and methyl 8-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (687 mg, 1 eq, 2.67 mmol) dissolved in THF (6.7 mL, 0.4 M) was added. The mixture was stirred for 1 h at room temperature under nitrogen. 3-Fluorobenzenesulfonyl chloride (391.5 μL, 1.1 eq, 2.94 mmol) was added and stirred at room temperature for 10 min. After quenching the reaction with H2O, the mixture was extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography (20% EtOAc / Hex) to obtain methyl 1-((3-fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (brown solid, 845 mg, yield 79%).

[0517] 1 H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 1 H), 7.62 - 7.72 (m, 3 H), 7.57 (dt,J=7.45, 1.62 Hz, 1 H), 7.27 (d,J=2.60 Hz, 1 H), 7.17 (d,J=8.41 Hz, 1 H), 6.76 (dd,J=8.25, 2.60 Hz, 1 H), 3.78 (s, 3 H), 3.71 (s, 3 H), 2.69 - 2.77 (m, 2 H), 2.53 - 2.61 (m, 2 H); MH + 416

[0518]

[0519] Step 5: (1-((3-fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (83)

[0520] Methyl 1-((3-fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (845 mg, 1 eq, 2.03 mmol) was dissolved in THF (10.2 mL, 0.2 M) and stirred at 0°C under nitrogen for 10 minutes. 1M DIBAL-H in toluene (6.1 mL, 3 eq, 6.1 mmol) was added and stirred at 0°C for 5 minutes. 1M hydrochloric acid aqueous solution was added to terminate the reaction, and sodium potassium tartrate tetrahydrate aqueous solution was added. The mixture was extracted twice with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a concentrated residue of (1-((3-fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (yellow oil 802 mg, 102%).

[0521] 1 H NMR (500 MHz, DMSO-d6) δ 7.54 - 7.63 (m, 2 H), 7.36 - 7.41 (m, 2 H), 7.32 (d,J=2.60 Hz, 1 H), 7.30 (s, 1 H), 7.15 (d,J=8.25 Hz, 1 H), 6.73 (dd,J=8.18, 2.67 Hz, 1 H), 4.98 (br s, 1 H), 4.30 (s, 2 H), 3.73 (s, 3 H), 2.50 - 2.54 (m, 2 H), 2.35 - 2.41 (m, 2 H); MH + 388

[0522]

[0523] Step 6: 1-((3-fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (84)

[0524] (1-((3-Fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol concentrated residue (802 mg, 1 eq, 2.03 mmol) was dissolved in acetonitrile (10.2 mL, 0.2 M), and 1.2 g of molecular sieve 4Å was added, followed by 4-methylmorpholine N-oxide (145.7 mg, 1.01 eq, 2.05 mmol) and TPAP (107.2 mg, 0.2 eq, 0.3 mmol) and stirred at room temperature for 3 hours. After completion of the reaction, Celite ® The mixture was filtered, and the filtrate was quenched with H2O. The mixture was extracted twice with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by normal phase silica gel column chromatography (20% EtOAc / Hex) to obtain 1-((3-fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (384 mg of a sticky brown solid, yield 49%).

[0525] 1 H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1 H), 8.45 (s, 1 H), 7.63 - 7.72 (m, 3 H), 7.58 (dt,J=7.57, 1.57 Hz, 1 H), 7.28 (d,J=2.60 Hz, 1 H), 7.16 (d,J=8.41 Hz, 1 H), 6.76 (dd,J=8.25, 2.60 Hz, 1 H), 3.71 (s, 3 H), 2.71 - 2.77 (m, 2 H), 2.53 - 2.60 (m, 2 H); MH + 386

[0526]

[0527] Step 7: 1-(1-((3-fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (85)

[0528] 1-((3-Fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (384 mg, 1 eq, 1.00 mmol) was dissolved in methanol (5 mL, 0.2 M), 2M MeNH2 (1 mL, 2 eq, 1.99 mmol) was added, and the mixture was stirred at room temperature for 1 h. After lowering the reaction mixture to 0°C, sodium borohydride (18.9 mg, 0.5 eq, 0.50 mmol) was added, and the mixture was stirred at room temperature for 10 min. The reaction was quenched with H2O, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by normal silica gel column chromatography (10-15% MeOH / DCM) gave 1-(1-((3-fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (yellow gel 358 mg, yield 90%).

[0529] 1 H NMR (500 MHz, DMSO-d6) δ 7.53 - 7.62 (m, 2 H), 7.36 - 7.41 (m, 2 H), 7.36 (s, 1 H), 7.32 (d,J=2.60 Hz, 1 H), 7.15 (d,J=8.25 Hz, 1 H), 6.73 (dd,J=8.25, 2.60 Hz, 1 H), 3.74 (s, 3 H), 3.52 (s, 2 H), 2.50 - 2.53 (m, 2 H), 2.36 - 2.42 (m, 2 H), 2.21 (s, 3 H),

[0530] 1H NMR (500 MHz, MeOH-d4) δ 7.56 (d,J=2.60 Hz, 1 H), 7.42 - 7.48 (m, 1 H), 7.38 - 7.42 (m, 2 H), 7.33 - 7.38 (m, 1 H), 7.29 (dt,J=8.25, 2.06 Hz, 1 H), 7.11 (d,J=8.25 Hz, 1 H), 6.73 (dd,J=8.25, 2.60 Hz, 1 H), 3.83 (s, 3 H), 3.64 (d,J=0.61 Hz, 2 H), 2.51 - 2.57 (m, 2 H), 2.40 - 2.44 (m, 2 H), 2.40 (s, 3 H); MH + 401

[0531]

[0532] [Example 15] 1-((3-fluorophenyl)sulfonyl)-3-((methylamino)methyl)-4,5-dihydro-1H-benzo[g]indole-8-ol (86)

[0533]

[0534] 1-(1-((3-Fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (242 mg, 0.60 mmol, 1 eq) was dissolved in DCM (2 mL, 0.3 M) and stirred at 0°C for 5 min. 1 M BBr3 (906 μL, 1.5 eq) was added and stirred at room temperature for 3 h. After completion of the reaction, the mixture was alkalized with 1 N NaOH and extracted twice with DCM. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by amine silica gel column chromatography (2-10% MeOH / DCM) to give 1-((3-fluorophenyl)sulfonyl)-3-((methylamino)methyl)-4,5-dihydro-1H-benzo[g]indol-8-ol (153 mg of orange sticky solid, yield 66%).

[0535] 1H NMR (500 MHz, MeOH-d4) δ 7.46 (d,J=2.45 Hz, 1 H), 7.39 - 7.45 (m, 2 H), 7.29 - 7.36 (m, 3 H), 7.02 (d,J=8.10 Hz, 1 H), 6.59 (dd,J=8.02, 2.52 Hz, 1 H), 3.53 (d,J=0.92 Hz, 2 H), 2.47 - 2.53 (m, 2 H), 2.35 - 2.41 (m, 2 H), 2.32 (s, 3 H); MH + 387

[0536]

[0537] [Example 16] 1-(1-((3-fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (94)

[0538]

[0539] Step 1: 5-Methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (88)

[0540] 5-Methoxy-3,4-dihydronaphthalen-1(2H)-one (500 mg, 1 eq), hydroxylamine HCl, and sodium acetate were dissolved in ethanol / H2O (1:1, 15.57 mL, 0.17 M), heated to 90°C, and stirred for 4 hours. After lowering the temperature to room temperature, ethyl acetate was added to the reaction solution, diluted, and washed several times with distilled water. The extracted organic layer was separated by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain 5-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime. The synthesized compound was used in the next reaction without any additional purification process (1230 mg of white solid, crude). MH + 192

[0541]

[0542] Step 2: Methyl 3-(((5-methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (89)

[0543] 5-Methoxy-3,4-dihydronaphthalen-1(2H)-one oxime was dissolved in DMSO, and TEA was slowly added at room temperature. Methyl propiolate (2 eq) dissolved in DMSO (1.03 mL, 2.5 M) was slowly added, and the mixture was stirred at room temperature for 20 min. EtOAc was added to the reaction solution, diluted, and washed several times with distilled water and brine. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain methyl 3-(((5-methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (yellow sticky oil, 1700 mg, crude). MH + 276

[0544]

[0545] Step 3: Methyl 6-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (90)

[0546] Methyl 3-(((5-methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)amino)oxy)acrylate (1700 mg, 1 eq) was dissolved in 1,4-dioxane (23.35 mL, 0.1 M), DBU (1.40 mL, 4 eq) was added, heated to 110°C, and stirred for 17 hours. After lowering the temperature to room temperature, EtOAc was added to the reaction solution, diluted, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 6-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (pink solid 820 mg, yield 63%). MH + 258

[0547]

[0548] Step 4: Methyl 1-((3-fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (91)

[0549] 60% sodium hydride (1.5 eq) in mineral oil was dissolved in THF (0.4 M), then methyl 6-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (1 eq) dissolved in THF (1.36 mL, 0.4 M) was slowly added, and the mixture was stirred at room temperature for 2 hours. 3-Fluorobenzenesulfonyl chloride (1.1 eq) was added, and the mixture was stirred at room temperature for 5 hours. The reaction was stopped by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4, and then filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((3-fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate (orange sticky gum 300 mg, yield 47%). MH + 416

[0550]

[0551] Step 5: (1-((3-fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (92)

[0552] Methyl 1-((3-fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carboxylate was dissolved in THF (2.19 mL, 0.2 M) and the temperature was lowered to 0℃. 1M DIBAL-H in toluene was slowly added and stirred at 0℃ for 20 minutes. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water and a saturated aqueous solution of potassium sodium tartrate. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1-((3-fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol. The synthesized compound was used in the following reaction without any separate purification process (purple sticky oil, crude). MH + 388

[0553]

[0554] Step 6: 1-((3-fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (93)

[0555] (1-((3-Fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)methanol (1 eq) was dissolved in MeCN (2.18 mL, 0.2 M), and molecular sieve 4Å (513 mg) was added and dried. N-Methylmorpholine N-oxide (1.5 eq) and TPAP (0.15 eq) were added and stirred at room temperature for 20 min. The molecular sieve 4Å was removed by filtration, washed with EtOAc, and then with distilled water. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((3-fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (136 mg of pink solid, 76% yield in two steps). MH + 386

[0556]

[0557] Step 7: 1-(1-((3-fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (94)

[0558] 1-((3-Fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indole-3-carbaldehyde (128 mg, 1 eq) was dissolved in MeOH (1.58 mL, 0.2 M), and 2 M methylamine solution in MeOH (0.40 mL, 2.5 eq) was added and stirred at room temperature for 1 hour and 30 minutes. After lowering the temperature to 0°C, NaBH4 (6 mg, 0.5 eq) was added and stirred at 0°C for 20 minutes. The reaction was terminated by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(1-((3-fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine (yellow solid, 102 mg, yield 82%).

[0559] 1 H NMR (500 MHz, DMSO-d6) δ 7.53 - 7.60 (m, 2 H), 7.29 - 7.43 (m, 4 H), 7.20 - 7.24 (m, 1 H), 6.90 - 6.94 (m, 1 H), 3.79 - 3.81 (m, 3 H), 3.56 - 3.66 (m, 3 H), 2.54 - 2.59 (m, 2 H), 2.34 - 2.41 (m, 2 H), 2.26 (s, 2 H); MH + 401

[0560]

[0561] [Example 17] 1-(1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (103)

[0562]

[0563] Step 1: 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-5-one oxime (96)

[0564] 1-Benzosuberone (20 g, 1 eq), hydroxylamine HCl (9.54 g, 1.1 eq), and sodium acetate (15.4 g, 1.5 eq) were dissolved in ethanol / H2O (1:1, 756 mL, 0.17 M), heated to 90°C, and stirred for 4 hours. After lowering the temperature to room temperature, ethyl acetate was added to the reaction solution, diluted, and washed several times with distilled water and then brine. The extracted organic layer was separated by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one oxime. The synthesized compound was used in the next reaction without a separate purification process (yellow solid 22 g, crude, 10:1 mixture of E / Z isomer).

[0565] 1 H NMR (500 MHz, MeOH-d4) for the major (E)-isomer δ 7.30 (ddd,J=16.20, 7.41, 1.45 Hz, 2 H), 7.19 - 7.23 (m, 1 H), 7.15 (dd,J=7.41, 0.69 Hz, 1 H), 2.72 - 2.76 (m, 2 H), 2.67 - 2.72 (m, 2 H), 1.77 (quin,J=6.57 Hz, 2 H), 1.61 (quin,J=6.23 Hz, 2 H), Partial 1 H NMR for the minor (Z)-isomer δ 2.39 - 2.43 (m, 2 H); MH + 176.

[0566]

[0567] Step 2: Methyl 3-(((6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ylidene)amino)oxy) acrylate (97)

[0568] 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-5-one oxime (22 g, 1 eq) was dissolved in DMSO (125 mL, 1 M), TEA (17.4 mL, 1 eq) was slowly added, and the temperature was lowered to 0℃. Methyl propiolate (22.2 mL, 2 eq) was dissolved in DMSO (49.9 mL, 2.5 M), and slowly added, and stirred at room temperature for 40 min. MC was added to the reaction solution, diluted, and washed several times with distilled water and brine. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 3-(((6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ylidene)amino)oxy)acrylate (yellow oil 32.2 g, quantitative in 2 steps, 77:8:15:0 ​​mixture of (E / Z) / (E / Z) isomer)

[0569] 1 H NMR (500 MHz, MeOH-d4) δ for the major (E) / (E)-isomer 8.07 (d,J=12.53 Hz, 1 H), 7.34 - 7.44 (m, 2 H), 7.25 - 7.30 (m, 1 H), 7.21 (d,J=7.64 Hz, 1 H), 5.62 (d,J=12.53 Hz, 1 H), 3.71 (s, 3 H), 2.73 - 2.84 (m, 4 H), 1.80 (quin,J=6.57 Hz, 2 H), 1.60 - 1.70 (m, 2 H), Partial 1 H NMR for the minor (E) / (Z)-isomer δ 7.91 (d,J=12.53 Hz, 1 H), 5.46 (d,J=12.53 Hz, 1 H), Partial 1 H NMR for the minor (Z) / (E)-isomer δ 7.53 (d,J=7.34 Hz, 1 H), 4.95 (d,J=7.34 Hz, 1 H); MH + 260

[0570]

[0571] Step 3: Methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (98)

[0572] Methyl 3-(((6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ylidene)amino)oxy)acrylate (32.2 g, 1 eq) was dissolved in 1,4-dioxane (1242 mL, 0.1 M), DBU (74.3 mL, 4 eq) was added, heated to 110°C, and stirred for 14 h. After lowering the temperature to room temperature, ethyl acetate was added to the reaction solution, diluted, and washed several times with distilled water and then brine. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and filtered using silica gel column chromatography. After concentrating the filtrate under reduced pressure, EtOAc was added, and the precipitated solid was filtered, washed with Hex, and purified to obtain methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (ivory solid 13.3 g, yield 44%).

[0573] 1 H NMR (500 MHz, MeOH-d4) δ 7.46 - 7.50 (m, 2 H), 7.21 (td,J=7.49, 1.53 Hz, 1 H), 7.12 - 7.16 (m, 1 H), 7.07 - 7.12 (m, 1 H), 3.78 (s, 3 H), 3.07 (t,J=6.88 Hz, 2 H), 2.76 - 2.80 (m, 2 H), 1.96 - 2.03 (m, 2 H); MH + 242

[0574]

[0575] Step 4: Methyl 1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (99)

[0576] 60% sodium hydride (23.6 mg, 1.5 eq) in mineral oil was dissolved in DMF (1.0 mL, 0.4 M), then methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (95 mg, 1 eq) dissolved in DMF (1.0 mL, 0.4 M) was slowly added, and the mixture was stirred at room temperature for 40 minutes. 3-Fluorobenzenesulfonyl chloride (0.06 mL, 1.1 eq) was slowly added, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4, and then filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (130 mg of white solid, yield 74%).

[0577] 1 H NMR (500 MHz, MeOH-d4) δ 8.05 (s, 1 H), 7.59 - 7.64 (m, 1 H), 7.30 - 7.43 (m, 4 H), 7.19 (t,J=6.01 Hz, 2 H), 6.97 (dt,J=8.02, 2.00 Hz, 1 H), 3.85 (s, 3 H), 3.14 - 3.26 (m, 1 H), 2.13 - 2.33 (m, 1 H), 1.87 - 2.05 (m, 2 H), 1.69 - 1.86 (m, 1 H), 1.25 - 1.41 (m, 1 H); MH + 400

[0578]

[0579] Step 5: (1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (100)

[0580] Methyl 1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (130 mg, 1 eq) was dissolved in THF (1.63 mL, 0.2 M) and the temperature was lowered to 0℃. 1M DIBAL-H in toluene (0.98 mL, 3 eq) was slowly added and stirred at 0℃ for 30 minutes. The reaction was quenched by adding 1N HCl aqueous solution, diluted with ethyl acetate, and washed several times with distilled water and a saturated aqueous solution of potassium sodium tartrate. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. After concentrating the filtrate under reduced pressure, (1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol was obtained. The synthesized compound was used in the next reaction without a separate purification process (133 mg of a pink sticky solid, crude).

[0581] 1 H NMR (500 MHz, MeOH-d4) δ 7.57 (dd,J=7.45, 1.15 Hz, 1 H), 7.35 - 7.40 (m, 2 H), 7.29 - 7.34 (m, 2 H), 7.27 (td,J=7.45, 1.72 Hz, 1 H), 7.19 (dd,J=7.45, 1.15 Hz, 1 H), 7.16 (dt,J=7.45, 1.43 Hz, 1 H), 6.97 (dt,J=8.16, 2.22 Hz, 1 H), 4.48 (s, 2 H), 2.37 - 2.64 (m, 1 H), 2.11 - 2.36 (m, 1 H), 1.68 - 2.09 (m, 3 H), 1.37 - 1.63 (m, 1 H); MH + 372

[0582]

[0583] Step 6: 1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (101)

[0584] (1-((3-Fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (120 mg, 1 eq) was dissolved in MeCN (1.62 mL, 0.2 M), and molecular sieve 4Å (348 mg) was added and dried. N-Methylmorpholine N-oxide (53 mg, 1.5 eq) and TPAP (17 mg, 0.15 eq) were added and stirred at room temperature for 30 min. Celite ® The organic layer was filtered and washed with EtOAc, then distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (88 mg of pink solid, 73% yield in two steps).

[0585] 1 H NMR (500 MHz, MeOH-d4) δ 9.93 (s, 1 H), 8.26 (s, 1 H), 7.64 (dd,J=7.73, 1.43 Hz, 1 H), 7.29 - 7.44 (m, 4 H), 7.23 (dt,J=7.73, 1.29 Hz, 1 H), 7.19 (dd,J=7.45, 1.15 Hz, 1 H), 7.03 (dt,J=8.16, 2.22 Hz, 1 H), 2.17 - 2.33 (m, 1 H), 1.90 - 2.03 (m, 3 H), 1.73 - 1.89 (m, 1 H), 1.27 - 1.47 (m, 1 H); MH + 370

[0586]

[0587] Step 7: 1-(1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (102)

[0588] 1-((3-Fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (85 mg, 1 eq) was dissolved in MeOH (1.15 mL, 0.2 M), and a 2 M methylamine solution in MeOH (0.29 mL, 2.5 eq) was added. The mixture was stirred at room temperature for 1 h. After lowering the temperature to 0°C, NaBH4 (4.4 mg, 0.5 eq) was added and stirred at room temperature for 20 min. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. After concentrating the filtrate under reduced pressure, 1-(1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine was obtained. The synthesized compound was used in the next reaction without a separate purification process (90 mg of brown sticky oil, crude).

[0589] 1 H NMR (500 MHz, MeOH-d4) δ 7.57 (dd,J=7.73, 1.43 Hz, 1 H), 7.42 (s, 1 H), 7.37 (dd,J=8.02, 5.16 Hz, 1 H), 7.30 - 7.35 (m, 2 H), 7.25 - 7.30 (m, 1 H), 7.18 - 7.21 (m, 1 H), 7.15 - 7.18 (m, 1 H), 6.98 (dt,J=8.02, 2.00 Hz, 1 H), 3.62 (s, 2 H), 2.40 (s, 3 H), 2.36 - 2.52 (m, 1) H), 2.13 - 2.36 (m, 1 H), 1.71 - 2.09 (m, 3 H), 1.32 - 1.58 (m, 1 H); MH + 385

[0590]

[0591] Step 8: 1-(1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (103)

[0592] 1-(1-((3-Fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (85 mg, 1 eq) was dissolved in ethyl acetate (2.21 mL, 0.1 M) and cooled to 0°C. 1N HCl in EtOAc (0.44 mL, 2.0 eq) was added at 0°C, and the temperature was increased to room temperature and stirred at room temperature for 30 minutes. The resulting solid was filtered with ethyl acetate to obtain 1-(1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (74 mg of white solid, 76% yield in two steps).

[0593] 1 H NMR (500 MHz, MeOH-d4) δ 7.70 (s, 1 H), 7.59 (dd,J=7.73, 1.43 Hz, 1 H), 7.29 - 7.42 (m, 4 H), 7.21 (dd,J=7.16, 1.43 Hz, 1 H), 7.17 (dt,J=7.45, 1.43 Hz, 1 H), 7.00 (dt,J=8.16, 2.22 Hz, 1 H), 4.11 (s, 2 H), 2.71 (s, 3 H), 2.38 - 2.60 (m, 1 H), 2.14 - 2.37 (m, 1 H), 1.83 - 2.11 (m, 3 H), 1.27 - 1.60 (m, 1 H); MS m / z 385 (MH + - HCl)

[0594]

[0595] [Example 18] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (107)

[0596]

[0597] Step 1: Methyl 1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (104)

[0598] 60% sodium hydride (1.24 g, 1.5 eq) in mineral oil was dissolved in anhydrous THF (52 mL, 0.4 M), then methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (5 g, 1 eq) dissolved in anhydrous THF (52 mL, 0.4 M) was slowly added, and the mixture was stirred at room temperature for 2 hours. Pyridine-3-sulfonyl chloride (2.72 mL, 1.1 eq) was slowly added, and the mixture was stirred at room temperature for 2 hours. After lowering the temperature to 0°C, distilled water was added to terminate the reaction, and ethyl acetate was added to dilute, and then distilled water was washed several times. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by amine column chromatography to obtain methyl 1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (7.2 g of white foam, yield 90%).

[0599] 1H NMR (500 MHz, MeOH-d4) δ 8.70 (dd,J=4.89, 1.53 Hz, 1 H), 8.36 (dd,J=2.45, 0.61 Hz, 1 H), 8.09 (s, 1 H), 7.73 - 7.77 (m, 1 H), 7.63 (dd,J=7.64, 1.38 Hz, 1 H), 7.41 (ddd,J=8.10, 4.89, 0.76 Hz, 1 H), 7.31 - 7.39 (m, 2 H), 7.18 (dd,J=7.41, 1.15 Hz, 1 H), 3.85 (s, 3 H), 3.18 - 3.26 (m, 1 H), 2.17 - 2.29 (m, 1 H), 1.87 - 2.05 (m, 2 H), 1.71 - 1.87 (m, 1 H), 1.19 - 1.36 (m, 1 H); MH + 383

[0600]

[0601] Step 2: (1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (105)

[0602] Methyl 1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (5.05 g, 1 eq) was dissolved in THF (66 mL, 0.2 M) and the temperature was lowered to 0°C. 1M DIBAL-H in toluene (40 mL, 3 eq) was slowly added and stirred at 0°C for 40 minutes. Distilled water was added to terminate the reaction and Celite was used. ® The residue was filtered and washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol. The synthesized compound was used in the next reaction without a separate purification process (yellow foam 4.6 g, crude).

[0603] 1 H NMR (400 MHz, MeOD-d4) δ 8.68 (dd,J=4.89, 1.68 Hz, 1 H), 8.34 - 8.37 (m, 1 H), 7.70 - 7.74 (m, 1 H), 7.59 (dd,J=7.57, 1.30 Hz, 1 H), 7.42 (s, 1 H), 7.40 (ddd,J=8.14, 4.93, 0.69 Hz, 1 H), 7.31 - 7.35 (m, 1 H), 7.28 (td,J=7.41, 1.38 Hz, 1 H), 7.19 (dd,J=7.57, 1.15 Hz, 1 H), 4.48 (s, 2 H), 2.38 - 2.68 (m, 1 H), 2.07 - 2.35 (m, 1 H), 1.75 - 2.06 (m, 3 H), 1.19 - 1.60 (m, 1 H); MH + 355

[0604]

[0605] Step 3: 1-(Pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (106)

[0606] (1-(Pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (4.6 g, 1 eq) was dissolved in MeCN (65 mL, 0.2 M), and molecular sieve 4Å (13.3 g) was added and dried. N-Methylmorpholine N-oxide (2.28 g, 1.5 eq) and TPAP (684 mg, 0.15 eq) were added and stirred at room temperature for 30 minutes. Celite ® The organic layer was filtered and washed with EtOAc, then distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (2.02 g of red sticky oil, 43% yield in two steps).

[0607] 1 H NMR (400 MHz, MeOD-d4) δ 9.94 (s, 1 H), 8.71 (dd,J=4.89, 1.53 Hz, 1 H), 8.41 (dd,J=2.45, 0.76 Hz, 1 H), 8.30 (s, 1 H), 7.78 (ddd,J=8.14, 2.41, 1.53 Hz, 1 H), 7.65 (dd,J=7.64, 1.38 Hz, 1 H), 7.41 (ddd,J=8.21, 4.93, 0.76 Hz, 1 H), 7.36 - 7.40 (m, 1 H), 7.32 - 7.36 (m, 1 H), 7.18 (dd,J=7.41, 1.15 Hz, 1 H), 3.15 - 3.27 (m, 1 H), 2.11 - 2.34 (m, 1 H), 1.89 - 2.06 (m, 2 H), 1.70 - 1.89 (m, 1 H), 1.26 - 1.42 (m, 1 H); MH + 353

[0608]

[0609] Step 4: N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (107)

[0610] 1-(Pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (2.02 g, 1 eq) was dissolved in MeOH (29 mL, 0.2 M), and a 2 M methylamine solution in MeOH (7.16 mL, 2.5 eq) was added. The mixture was stirred at room temperature for 1 hour and 30 minutes. After lowering the temperature to 0°C, NaBH4 (108 mg, 0.5 eq) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by amine silica gel column chromatography to obtain N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (red sticky oil 1.73 g, yield 82%).

[0611] 1 H NMR (400 MHz, MeOD-d4) δ 8.68 (dd,J=4.89, 1.53 Hz, 1 H), 8.36 (d,J=1.83 Hz, 1 H), 7.72 - 7.76 (m, 1 H), 7.58 (dd,J=7.64, 1.22 Hz, 1 H), 7.43 (s, 1 H), 7.40 (ddd,J=8.10, 4.89, 0.76 Hz, 1 H), 7.31 - 7.35 (m, 1 H), 7.28 (td,J=7.41, 1.38 Hz, 1 H), 7.19 (dd,J=7.49, 1.07 Hz, 1 H), 3.57 (d,J=0.76 Hz, 2 H), 2.37 (s, 3 H), 2.10 - 2.33 (m, 1 H), 1.75 - 2.08 (m, 4 H), 1.23 - 1.49 (m, 1 H); MH + 368

[0612]

[0613] [Example 19] N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine fumarate (108)

[0614]

[0615] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (3.74 g, 1 eq) was dissolved in ethyl acetate (51 mL, 0.2 M), fumaric acid (1.18 g, 1 eq) was added, and the mixture was stirred at room temperature for 4 hours. The resulting solid was filtered with ethyl acetate to obtain N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine fumarate (pale pink solid 4.67 g, yield 94%).

[0616] 1 H NMR (500 MHz, MeOH-d4) δ 8.70 (dd,J=4.89, 1.53 Hz, 1 H), 8.39 (dd,J=2.45, 0.61 Hz, 1 H), 7.73 (s, 1 H), 7.70 (ddd,J=8.14, 2.41, 1.53 Hz, 1 H), 7.60 (dd,J=7.57, 1.45 Hz, 1 H), 7.40 (ddd,J=8.18, 4.89, 0.84 Hz, 1 H), 7.34 - 7.38 (m, 1 H), 7.30 - 7.34 (m, 1 H), 7.20 (dd,J=7.34, 1.22 Hz, 1 H), 6.69 (s, 2 H), 4.11 (s, 2 H), 2.71 (s, 3 H), 2.39 - 2.58 (m, 1 H), 2.13 - 2.35 (m, 1 H), 1.80 - 2.12 (m, 3 H), 1.19 - 1.46 (m, 1 H), MS m / z 368 (MH + - C4H4O4)

[0617]

[0618] [Example 20] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine dihydrochloride (109)

[0619]

[0620] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (150 mg, 1 eq) was dissolved in ethyl acetate (2 mL, 0.2 M), 1 N HCl in EtOAc (1.02 mL, 2.5 eq) was added, and the mixture was stirred at room temperature for 2 h. The resulting solid was filtered with ethyl acetate to obtain N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine dihydrochloride (brown solid, 150 mg, yield 83%).

[0621] 1 H NMR (399 MHz, MeOH-d4) δ 8.71 (dd,J=4.79, 1.47 Hz, 1 H), 8.41 (d,J=2.35 Hz, 1 H), 7.74 (s, 1 H), 7.68 - 7.73 (m, 1 H), 7.61 (dd,J=7.53, 1.47 Hz, 1 H), 7.39 - 7.44 (m, 1 H), 7.30 - 7.39 (m, 2 H), 7.19 - 7.23 (m, 1 H), 4.13 (s, 2 H), 2.72 (s, 3 H), 2.40 - 2.60 (m, 1 H), 2.18 - 2.35 (m, 1 H), 1.85 - 2.11 (m, 3 H), 1.21 - 1.41 (m, 1 H); MS m / z 368 (MH + - 2HCl)

[0622]

[0623] [Example 21] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine 2-hydroxysuccinate (110)

[0624]

[0625] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (100 mg, 1 eq) was dissolved in ethyl acetate (1 mL, 10 v / w), malic acid (33.6 mg, 1.1 eq) was added, and the mixture was stirred at room temperature for 18 hours. The resulting solid was washed with ethyl acetate and dried to obtain N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine 2-hydroxysuccinate (white solid 121 mg, yield 88.6%).

[0626] 1 H NMR (500 MHz, DMSO-d6) δ 8.81 (dd,J=4.81, 1.45 Hz, 1 H), 8.40 (d,J=2.29 Hz, 1 H), 7.68 (dt,J=8.48, 1.87 Hz, 1 H), 7.66 (s, 1 H), 7.47 - 7.52 (m, 2 H), 7.28 - 7.37 (m, 2 H), 7.23 (dd,J=7.49, 1.07 Hz, 1 H), 3.94 (s, 2 H), 3.89 (dd,J=9.93, 4.13 Hz, 1 H), 2.49 (s, 3 H), 2.32 (dd,J=15.51, 4.05 Hz, 1 H), 1.88 - 1.95 (m, 2 H); MS m / z 368 (MH + - C4H6O5)

[0627]

[0628] [Example 22] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine 2,3-dihydroxysuccinate (111)

[0629]

[0630] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (100 mg, 1 eq) was dissolved in ethyl acetate (1 mL, 10 v / w), tartaric acid (43.7 mg, 1.1 eq) was added, and the mixture was stirred at room temperature for 18 hours. The resulting solid was washed with ethyl acetate and dried to obtain N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine 2,3-dihydroxysuccinate (white solid 126 mg, yield 89.4%).

[0631] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.80 (dd,J= 4.89, 1.53 Hz, 1 H), 8.39 (d,J=2.29 Hz, 1 H), 7.71 (dt,J=8.18, 1.95 Hz, 1 H), 7.67 (s, 1 H), 7.50 - 7.53 (m, 1 H), 7.46 - 7.50 (m, 1 H), 7.27 - 7.36 (m, 2 H), 7.23 (d,J=7.49 Hz, 1 H), 3.95 (s, 2 H), 3.92 (s, 2 H), 2.47 (s, 3 H), 1.99 (s, 1 H), 1.87 - 1.96 (m, 2H), 1.17 (t,J=7.11 Hz, 1 H); MS m / z 368 (MH + - C4H6O6)

[0632]

[0633] [Example 23] N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine difumarate (112)

[0634]

[0635] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (4.43 g, 1 eq) was dissolved in ethyl acetate (60 mL, 0.2 M), fumaric acid (1.4 g, 1 eq) was added, and the mixture was stirred at room temperature for 2 hours. The resulting solid was filtered with ethyl acetate to obtain N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine difumarate (white solid 3.24 g, yield 45%).

[0636] 1 H NMR (500 MHz, DMSO-d6) δ 8.80 (dd,J=4.74, 1.53 Hz, 1 H), 8.38 (dd,J=2.45, 0.61 Hz, 1 H), 7.71 (ddd,J=8.10, 2.45, 1.53 Hz, 1 H), 7.69 (s, 1 H), 7.46 - 7.51 (m, 2 H), 7.27 - 7.36 (m, 2 H), 7.22 (dd,J=7.49, 1.22 Hz, 1 H), 6.55 (s, 4 H), 3.94 (s, 2 H), 2.47 (s, 3 H), 2.06 - 2.34 (m, 1 H), 1.87 - 1.96 (m, 3 H), 1.52 - 1.86 (m, 1 H), 0.99 - 1.49 (m, 1 H); MS m / z 368 (MH + - 2C4H4O4)

[0637]

[0638] [Example 24] N-Methyl-1-(1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine hydrochloride (118)

[0639]

[0640] Step 1: Methyl 1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (114)

[0641] 60% sodium hydride (39.8 mg, 1.5 eq) in mineral oil was dissolved in DMF (1.66 mL, 0.4 M), and then methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (160 mg, 1 eq) dissolved in DMF (1.66 mL, 0.4 M) was slowly added and stirred at room temperature for 1 hour. 1-Methyl-1H-indole-4-sulfonyl chloride (168 mg, 1.1 eq) was added and stirred at room temperature for 1 hour. The reaction was terminated by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (white foam 260 mg, yield 90%).

[0642] 1H NMR (500 MHz, MeOH-d4) δ 8.17 (s, 1 H), 7.58 - 7.64 (m, 2 H), 7.25 - 7.30 (m, 2 H), 7.18 - 7.22 (m, 1 H), 6.97 - 7.02 (m, 2 H), 6.89 (t,J=8.02 Hz, 1 H), 6.41 - 6.45 (m, 1 H), 3.83 (s, 3 H), 3.80 (s, 3 H), 3.02 - 3.24 (m, 1 H), 1.51 - 2.08 (m, 4 H), 0.78 - 1.10 (m, 1) H); MH + 435

[0643]

[0644] Step 2: (1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (115)

[0645] Methyl 1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (255 mg, 1 eq) was dissolved in THF (2.93 mL, 0.2 M) and the temperature was lowered to 0℃. 1M DIBAL-H in toluene (1.76 mL, 3 eq) was slowly added and stirred at 0℃ for 20 minutes. The reaction was quenched by adding 1N HCl aqueous solution, diluted with ethyl acetate, and washed several times with distilled water and a saturated aqueous solution of potassium sodium tartrate. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. After concentrating the filtrate under reduced pressure, (1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol was obtained. The synthesized compound was used in the next reaction without a separate purification process (235 mg of ivory solid, crude).

[0646] 1H NMR (500 MHz, MeOH-d4) δ 7.55 - 7.61 (m, 2 H), 7.48 (s, 1 H), 7.23 - 7.27 (m, 1 H), 7.21 (d,J=2.86 Hz, 1 H), 7.18 (td,J=7.45, 1.15 Hz, 1 H), 7.02 - 7.07 (m, 2 H), 6.93 - 6.98 (m, 1 H), 6.41 - 6.46 (m, 1 H), 4.42 (s, 2 H), 3.79 (s, 3 H), 2.18 - 2.62 (m, 1 H), 1.55 - 2.14 (m, 4 H), 1.03 - 1.52 (m, 1 H); MH + 407

[0647]

[0648] Step 3: 1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (116)

[0649] (1-((1-Methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (235 mg, 1 eq) was dissolved in MeCN (2.89 mL, 0.2 M), and molecular sieve 4Å (682 mg) was added and dried. N-Methylmorpholine N-oxide (94.7 mg, 1.5 eq) and TPAP (30.5 mg, 0.15 eq) were added and stirred at room temperature for 20 min. Celite ® The organic layer was filtered and washed with EtOAc, then distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (beige solid 176 mg, two-step yield 75%).

[0650] 1H NMR (500 MHz, MeOH-d4) δ 9.89 (s, 1 H), 8.41 (s, 1 H), 7.64 (dd,J=7.73, 1.43 Hz, 1 H), 7.61 (d,J=8.02 Hz, 1 H), 7.26 - 7.31 (m, 2 H), 7.21 (td,J=7.45, 1.72 Hz, 1 H), 7.03 (d,J=6.87 Hz, 1 H), 6.99 (dd,J=7.45, 1.15 Hz, 1 H), 6.86 - 6.91 (m, 1 H), 6.47 - 6.51 (m, 1 H), 3.81 (s, 3 H), 1.54 - 2.10 (m, 5 H), 0.68 - 1.16 (m, 1 H); MH + 405

[0651]

[0652] Step 4: N-Methyl-1-(1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (117)

[0653] 1-((1-Methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (170 mg, 1 eq) was dissolved in MeOH (2.1 mL, 0.2 M), and a 2 M methylamine solution in MeOH (0.52 mL, 2.5 eq) was added. The mixture was stirred at room temperature for 1 hour and 40 minutes. After lowering the temperature to 0°C, NaBH4 (7.95 mg, 0.5 eq) was added, and the mixture was stirred at room temperature for 20 minutes. Afterwards, NaBH4 (7.95 mg, 0.5 eq) was additionally added, and the mixture was stirred at room temperature for 20 minutes. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain N-methyl-1-(1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (ivory-colored sticky solid, 106 mg, yield 60%).

[0654] 1 H NMR (500 MHz, MeOH-d4) δ 7.59 (dd,J=7.64, 1.22 Hz, 1 H), 7.55 - 7.58 (m, 1 H), 7.54 (s, 1 H), 7.26 (td,J=7.57, 1.38 Hz, 1 H), 7.21 (d,J=3.21 Hz, 1 H), 7.19 (td,J=7.41, 1.38 Hz, 1 H), 7.03 (dd,J=7.64, 0.76 Hz, 2 H), 6.91 - 6.96 (m, 1 H), 6.46 (dd,J=3.21, 0.76 Hz, 1 H), 3.79 (s, 3 H), 3.56 (s, 2 H), 2.31 (s, 3 H), 1.52 - 2.09 (m, 5 H), 0.97 - 1.31 (m, 1 H); MH + 420

[0655]

[0656] Step 5: N-Methyl-1-(1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine hydrochloride (118)

[0657] N-Methyl-1-(1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (100 mg, 1 eq) was dissolved in ethyl acetate (2.38 mL, 0.1 M) and cooled to 0°C. 1N HCl in EtOAc (0.36 mL, 1.5 eq) was added at 0°C, and the temperature was increased to room temperature and stirred at room temperature for 1 h. The reaction solution was concentrated and dried to obtain N-methyl-1-(1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine hydrochloride (purple solid 109 mg, 100% quantitative).

[0658] 1 H NMR (500 MHz, MeOH-d4) δ 7.82 (s, 1 H), 7.58 - 7.62 (m, 2 H), 7.25 - 7.30 (m, 2 H), 7.21 (td,J=7.49, 1.38 Hz, 1 H), 7.01 - 7.06 (m, 2 H), 6.90 - 6.95 (m, 1 H), 6.46 (dd,J=3.13, 0.84 Hz, 1 H), 4.06 (s, 2 H), 3.80 (s, 3 H), 2.64 (s, 3 H), 2.16 - 2.52 (m, 1 H), 1.65 - 2.12 (m, 4 H), 0.95 - 1.22 (m, 1 H); MS m / z 420 (MH + - HCl)

[0659]

[0660] [Example 25] 1-(1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (124)

[0661]

[0662]

[0663] Step 1: Methyl 1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (120)

[0664] Methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (250 mg) was added to a solution of sodium hydride (62 mg, 1.5 eq) in N,N-dimethylformamide (5.18 mL), and the mixture was stirred at room temperature for 30 minutes. 3-Chlorobenzenesulfonyl chloride (161 μL, 1.1 eq) was added to the reaction solution, and the mixture was stirred at room temperature for 20 minutes. After terminating the reaction by adding H2O, the mixture was diluted with ethyl acetate, and then washed several times with distilled water. The extracted organic layer was treated with Na2SO4. After drying using ethanol, the residue was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain methyl 1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (236 mg of white solid, yield 55%). MH + 416

[0665]

[0666] Step 2: (1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (121)

[0667] Methyl 1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (236 mg) was dissolved in THF (2.84 mL) and the solution was cooled to 0°C. 1 M DIBAL-H (1.70 mL, 3.0 eq) was added and stirred at 0°C for 40 minutes. After quenching the reaction with 1 N HCl, ethyl acetate was added to dilute the mixture and then distilled water was used to wash the extracted organic layer several times. Na2SO4 was added. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol. The synthesized compound was used in the following reaction without purification (purple solid, crude). MH + 388

[0668]

[0669] Step 3: 1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (122)

[0670] (1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (184 mg) was dissolved in a solution, (diacetoxyiodo)benzene (245 mg, 1.6 eq) and TEMPO (22.3 mg, 0.3 eq) were added, and the mixture was stirred at room temperature for 2 hours. CH2Cl2 was added to the reaction solution. After diluting, the solution was washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain 1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (brown oil 74 mg, yield 40%). MH +386

[0671]

[0672] Step 4: 1-(1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (123)

[0673] 2 M methylamine (220 μL, 2.5 eq) was added to a solution of 1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (68 mg) in methanol (881 μL), and the mixture was stirred at room temperature for 1 hour. After lowering the reaction solution to 0°C, NaBH4 (3.33 mg, 0.5 eq) was added, and the mixture was stirred at 0°C for 30 minutes. After quenching the reaction using 1 N HCl, the mixture was diluted with ethyl acetate, and then washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain 1-(1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (brown oil 65 mg, yield 92%). MH + 401

[0674]

[0675] Step 5: 1-(1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (124)

[0676] 1-(1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (65 mg) was dissolved in ethyl acetate (810 μL) and cooled to 0°C. 1 M HCl in ethyl acetate (320 μL, 2.0 eq) was added and stirred at room temperature for 2 hours. The reaction mixture was filtered under reduced pressure to obtain 1-(1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (white solid 52 mg, yield 74%).

[0677] 1 H NMR (500 MHz, DMSO-d6) δ 8.86 - 9.09 (m, 2 H), 7.69 - 7.74 (m, 2 H), 7.42 - 7.49 (m, 2 H), 7.26 - 7.36 (m, 3 H), 7.19 - 7.24 (m, 1 H), 7.09 (t,J=1.91 Hz, 1 H), 3.97 (br s, 2 H), 2.46 (br s, 3 H), 2.03 - 2.38 (m, 1 H), 1.89 (br dd,J=13.22, 6.50 Hz, 2 H), 1.54 - 1.81 (m, 1) H), 1.27 - 1.51 (m, 1 H); MS m / z 401 (MH + - HCl)

[0678]

[0679] [Example 26] 1-(1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (130)

[0680]

[0681] Step 1: Methyl 1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (126)

[0682] Methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (250 mg) was added to a solution of sodium hydride (62 mg, 1.5 eq) in N,N-dimethylformamide (5.18 mL), and the mixture was stirred at room temperature for 30 minutes. 4-Fluorobenzenesulfonyl chloride (104 μL, 1.1 eq) was added to the reaction solution, and the mixture was stirred at room temperature for 20 minutes. H2O was added to terminate the reaction, and the mixture was diluted with ethyl acetate and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain methyl 1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (yellow oil 300 mg, yield 72%). MH + 400

[0683]

[0684] Step 2: (1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (127)

[0685] Methyl 1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (300 mg) was dissolved in THF (3.76 mL) and cooled to 0°C. 1 M DIBAL-H (2.25 mL, 3.0 eq) was added to the solution and stirred at 0°C for 40 min. After quenching the reaction with 1 N HCl, the mixture was diluted with ethyl acetate and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol. The synthesized compound was used in the following reaction without purification (purple oil, crude). MH + 372

[0686]

[0687] Step 3: 1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (128)

[0688] (1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (277 mg) was dissolved in a solution, (diacetoxyiodo)benzene (384 mg, 1.6 eq) and TEMPO (35 mg, 0.3 eq) were added, and the mixture was stirred at room temperature for 2 hours. CH2Cl2 was added to the reaction solution. After diluting, the solution was washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain 1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (brown oil 170 mg, 62%). MH + 370

[0689]

[0690] Step 4: 1-(1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (129)

[0691] 1-((4-Fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (170 mg) was dissolved in methanol (2.30 mL), 2 M methylamine (580 μL, 2.5 eq) was added, and the mixture was stirred at room temperature for 1 hour. After lowering the reaction solution to 0°C, NaBH4 (8.70 mg, 0.5 eq) was added, and the mixture was stirred at 0°C for 30 minutes. After quenching the reaction using 1 N HCl, the mixture was diluted with ethyl acetate, and then washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain 1-(1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (82 mg of colorless oil, yield 46%). MH + 385

[0692]

[0693] Step 5: 1-(1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (130)

[0694] 1-(1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (82 mg) was dissolved in ethyl acetate (1.07 mL) and cooled to 0°C. 1 M HCl in ethyl acetate (430 μL, 2.0 eq) was added and stirred at room temperature for 2 hours. The reaction mixture was filtered under reduced pressure to obtain 1-(1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (white solid 65 mg, yield 74%).

[0695] 1 H NMR (500 MHz, DMSO-d6) δ 8.62 (br d,J=2.75 Hz, 1 H), 7.66 (s, 1 H), 7.43 (dd,J=7.49, 1.38 Hz, 1 H), 7.32 - 7.37 (m, 2 H), 7.23 - 7.32 (m, 5 H), 7.17 - 7.22 (m, 1 H), 3.96 (s, 2 H), 2.47 (br s, 3 H), 2.09 - 2.29 (m, 1 H), 1.86 - 1.93 (m, 2 H), 1.57 - 1.80 (m, 1 H), 1.27 - 1.51 (m, 1 H); MS m / z 385 (MH + - HCl)

[0696]

[0697] [Example 27] N-Methyl-1-(1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (135)

[0698]

[0699] Step 1: Methyl 1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (132)

[0700] Methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (250 mg) was added to a solution of sodium hydride (62 mg, 1.5 eq) in N,N-dimethylformamide (5.18 mL), and the mixture was stirred at room temperature for 30 minutes. 3-(Trifluoromethyl)benzenesulfonyl chloride (183 μL, 1.1 eq) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After quenching the reaction by adding H2O, the mixture was diluted with ethyl acetate, and then washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain methyl 1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (pink oil 410 mg, yield 87%).

[0701] 1 H NMR (500 MHz, DMSO-d6) δ 8.07 (br d,J=7.95 Hz, 1 H) 8.05 (d,J=0.92 Hz, 1 H) 7.91 (d,J=7.64 Hz, 1 H) 7.73 - 7.78 (m, 1 H) 7.54 (d,J=7.49 Hz, 1 H) 7.30 - 7.40 (m, 2 H) 7.29 (s, 1 H) 7.19 (d,J=7.34 Hz, 1 H) 3.79 (s, 3 H) 3.04 - 3.22 (m, 1 H) 2.09 - 2.28 (m, 1 H) 1.80 - 1.96 (m, 2H) 1.59 - 1.76 (m, 1 H) 1.06 - 1.26 (m, 1 H); MH + 450

[0702]

[0703] Step 2: (1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (133)

[0704] Methyl 1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (410 mg) was dissolved in THF (4.56 mL) and cooled to 0°C. 1M DIBAL-H (2.74 mL, 3.0 eq) was added to the solution and stirred at 0°C for 40 min. After quenching the reaction with 1N HCl, the mixture was diluted with ethyl acetate and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol. The synthesized compound was used in the following reaction without purification (yellow oil, crude).

[0705] 1 H NMR (500 MHz, DMSO-d6) δ 8.05 (d,J=7.49 Hz, 1 H) 7.73 - 7.81 (m, 2 H) 7.50 (dd,J=7.64, 1.22 Hz, 1 H) 7.31 - 7.37 (m, 2 H) 7.28 (td,J=7.41, 1.38 Hz, 1 H) 7.17 - 7.22 (m, 2 H) 4.98 (t,J=5.27 Hz, 1 H) 4.33 (d,J=4.74 Hz, 2 H) 2.31 - 2.47 (m, 1 H) 2.18 (br s, 1 H) 1.79 - 1.94 (m, 2H) 1.60 - 1.76 (m, 1 H); MH + 422

[0706]

[0707] Step 3: 1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (134)

[0708] (1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (401 mg) was dissolved in MeCN (4.55 mL), and molecular sieve 4Å (1.2 g), NMO (246 mg, 2.3 eq), and TPAP (48 mg, 0.15 eq) were added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was filtered through celite ® After filtration using , the filtrate was diluted with ethyl acetate and washed several times with distilled water. The extracted organic layer was dried using Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography to obtain 1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (orange oil 230 mg, yield 60%). MH + 420

[0709]

[0710] Step 4: N-Methyl-1-(1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (135)

[0711] 2 M methylamine (0.41 mL) was added to a solution of 1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (230 mg) in methanol (2.74 mL), and the mixture was stirred at room temperature for 1 hour. After lowering the reaction solution to 0°C, NaBH4 (10.4 mg, 0.5 eq) was added, and the mixture was stirred at 0°C for 10 minutes. The reaction solution was diluted with ethyl acetate and washed several times with distilled water. The extracted organic layer was separated by adding Na2SO4. After drying using, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by amino silica gel column chromatography to obtain N-methyl-1-(1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (yellow oil 162 mg, yield 68%).

[0712] 1 H NMR (500 MHz, DMSO-d6) δ 8.02 - 8.09 (m, 1 H), 7.70 - 7.78 (m, 2 H), 7.49 (dd,J=7.64, 1.22 Hz, 1 H), 7.31 - 7.38 (m, 2 H), 7.25 - 7.30 (m, 2 H), 7.21 (d,J=7.49 Hz, 1 H), 3.45 (s, 2 H), 2.33 - 2.46 (m, 1 H), 2.18 - 2.29 (m, 1 H), 2.16 (s, 3 H), 1.85 (br d,J=0.92 Hz, 2 H), 1.63 - 1.78 (m, 1 H); MH + 435

[0713]

[0714] [Example 28] 1-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (141)

[0715]

[0716] Step 1: Methyl 1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (137)

[0717] Methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (250 mg) was dissolved in DMF (5.2 mL), and 60% sodium hydride in mineral oil (62 mg) was added at 0°C. The reaction mixture was purged with nitrogen and stirred at room temperature for 30 minutes. 6-Chlorosulfonyl-1,4 benzodioxane (290 μL) was added at 0°C and stirred at room temperature for 30 hours. The reaction was terminated by adding distilled water at 0°C and extracted with EtOAc. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (orange oil 213 mg, yield 47.5%). MH + 440

[0718]

[0719] Step 2: (1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (138)

[0720] Methyl 1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (110 mg) was dissolved in THF (1.25 mL), and 1 M DIBAL-H in toluene (0.8 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched by adding 1 N HCl aqueous solution, and extracted with EtOAc. The extracted organic layer was washed with potassium sodium tartrate aqueous solution, and then Na2SO4 was added. The mixture was dried and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol. The synthesized compound was used in the next reaction without any separate purification process (orange oil, crude).

[0721] 1 H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1 H), 7.43 - 7.47 (m, 1 H), 7.26 - 7.33 (m, 2 H), 7.20 - 7.24 (m, 1 H), 6.79 - 6.87 (m, 2 H), 6.69 (d,J=2.14 Hz, 1 H), 4.22 - 4.27 (m, 2 H), 4.11 - 4.21 (m, 2 H), 3.74 (s, 2 H), 2.21 - 2.36 (m, 1 H), 1.79 - 1.98 (m, 2 H), 1.57 - 1.78 (m, 2 H), 1.33 - 1.56 (m, 1 H); MH + 412

[0722]

[0723] Step 3: 1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (139)

[0724] (1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (201 mg) was dissolved in acetonitrile (2.5 mL), and molecular sieve 4Å (600 mg) was added and stirred at room temperature. 4-Methylmorpholine N-oxide (80 mg) and tetrapropylammonium perruthenate (26 mg) were added to the reaction mixture and stirred at room temperature for 20 minutes. The reaction mixture was filtered through celite. ®The residue was filtered under reduced pressure and washed with EtOAc. The filtrate was diluted with EtOAc and washed with distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (orange oil 120 mg, yield 57%).

[0725] 1 H NMR (500 MHz, DMSO-d6) δ 9.89 (s, 1 H), 8.31 (s, 1 H), 7.43 - 7.48 (m, 1 H), 7.25 - 7.34 (m, 2 H), 7.20 - 7.24 (m, 1 H), 6.79 - 6.89 (m, 2 H), 6.72 (d,J=2.29 Hz, 1 H), 4.21 - 4.27 (m, 2 H), 4.18 (dd,J=3.59, 2.06 Hz, 2 H), 2.09 - 2.36 (m, 1 H), 1.84 - 1.98 (m, 3 H), 1.32 - 1.82 (m, 2 H); MH + 410

[0726]

[0727] Step 4: 1-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (140)

[0728] 1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (120 mg) was dissolved in MeOH (1.5 mL), 2M MeNH2 in MeOH (0.36 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After cooling the reaction to 0°C, sodium borohydride (5.5 mg) was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction was terminated by adding distilled water at 0°C, diluted with EtOAc, and washed with distilled water and brine. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (orange oil 103 mg, yield 83%).

[0729] 1 H NMR (500 MHz, DMSO-d6) δ 7.40 (dd,J=7.03, 1.07 Hz, 1 H), 7.22 - 7.27 (m, 1 H), 7.18 - 7.22 (m, 3 H), 6.83 (d,J=8.71 Hz, 1 H), 6.75 (dd,J=8.56, 2.29 Hz, 1 H), 6.60 (d,J=2.29 Hz, 1 H), 4.13 - 4.27 (m, 4 H), 3.42 (s, 2 H), 2.22 - 2.41 (m, 1 H), 2.18 (s, 3 H), 1.82 - 1.93 (m, 3 H), 1.34 - 1.80 (m, 2 H); MH + 424

[0730]

[0731] Step 5: 1-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (141)

[0732] 1-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (103 mg) was dissolved in EtOAc (2.4 mL), and 1 M HCl in EtOAc (0.36 mL) was added. The reaction was stirred at room temperature for 3 h. The resulting solid was filtered with EtOAc to obtain 1-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (80 mg of white solid, yield 72%).

[0733] 1 H NMR (500 MHz, DMSO-d6) δ 8.70 (br s, 1 H), 7.61 (s, 1 H), 7.39 - 7.44 (m, 1 H), 7.27 (quind,J=7.22, 1.68 Hz, 2 H), 7.18 - 7.23 (m, 1 H), 6.82 - 6.88 (m, 1 H), 6.74 - 6.81 (m, 1 H), 6.63 (d,J=2.29 Hz, 1 H), 4.21 - 4.26 (m, 2 H), 4.17 (dd,J=4.81, 2.37 Hz, 2 H), 3.97 (s, 2) H), 2.48 (s, 3 H), 2.07 - 2.39 (m, 1 H), 1.83 - 1.98 (m, 3 H), 1.33 - 1.83 (m, 2 H); MS m / z 424 (MH + - HCl)

[0734]

[0735] [Example 29] 1-(1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (147)

[0736]

[0737] Step 1: Methyl 1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (143)

[0738] 60% sodium hydride (125 mg, 1.5 eq) in mineral oil was dissolved in DMF (5.18 mL, 0.4 M), and then methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (500 mg, 1 eq) dissolved in DMF (5.18 mL, 0.4 M) was slowly added and stirred at room temperature for 2 hours. 3-Methoxybenzenesulfonyl chloride (0.323 mL, 1.1 eq) was added and stirred at room temperature for 1 hour. The reaction was terminated by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (orange sticky oil 748 mg, yield 79%).

[0739] 1H NMR (500 MHz, MeOH-d4) δ 8.03 (s, 1 H), 7.63 (dd,J=7.72, 1.30 Hz, 1 H), 7.33 - 7.37 (m, 1 H), 7.26 - 7.33 (m, 2 H), 7.18 (dd,J=7.41, 0.99 Hz, 1 H), 7.10 (ddd,J=8.41, 2.60, 0.92 Hz, 1 H), 6.99 (ddd,J=7.79, 1.83, 0.92 Hz, 1 H), 6.66 - 6.69 (m, 1 H), 3.84 (s, 3 H), 3.56 (s, 3 H), 3.10 - 3.26 (m, 1 H), 2.11 - 2.29 (m, 1 H), 1.86 - 2.05 (m, 2 H), 1.68 - 1.85 (m, 1 H), 1.27 - 1.44 (m, 1 H); MH + 412

[0740]

[0741] Step 2: (1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (144)

[0742] 1-((3-Methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (200 mg, 1 eq) was dissolved in THF (2.43 mL, 0.2 M) and the temperature was lowered to 0℃. 1M DIBAL-H in toluene (1.46 mL, 3 eq) was slowly added and stirred at 0℃ for 20 minutes. The reaction was quenched by adding 1N HCl aqueous solution, diluted with ethyl acetate, and washed several times with distilled water and a saturated aqueous solution of potassium sodium tartrate. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. After concentrating the filtrate under reduced pressure, (1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol was obtained. The synthesized compound was used in the next reaction without a separate purification process (184 mg of pink sticky oil, crude).

[0743] 1 H NMR (500 MHz, MeOH-d4) δ 7.59 (dd,J=7.64, 1.38 Hz, 1 H), 7.37 (s, 1 H), 7.31 (td,J=7.57, 1.53 Hz, 1 H), 7.23 - 7.27 (m, 2 H), 7.18 (dd,J=7.49, 1.22 Hz, 1 H), 7.07 (ddd,J=8.41, 2.60, 0.92 Hz, 1 H), 6.96 - 6.99 (m, 1 H), 6.67 - 6.70 (m, 1 H), 4.47 (s, 2 H), 3.57 (s, 3 H), 2.35 - 2.65 (m, 1 H), 2.07 - 2.34 (m, 1 H), 1.71 - 2.04 (m, 3 H), 1.38 - 1.65 (m, 1 H); MH + 384

[0744]

[0745] Step 3: 1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (145)

[0746] (1-((3-Methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (180 mg, 1 eq) was dissolved in MeCN (2.35 mL, 0.2 M), and molecular sieve 4Å (522 mg) was added and dried. N-Methylmorpholine N-oxide (76.9 mg, 1.5 eq) and TPAP (24.7 mg, 0.15 eq) were added and stirred at room temperature for 20 min. The molecular sieve 4Å was removed by filtration, washed with EtOAc, and then with distilled water. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (130 mg of pink sticky oil, 70% yield in two steps).

[0747] 1 H NMR (500 MHz, MeOH-d4) δ 9.92 (s, 1 H), 8.24 (s, 1 H), 7.65 (dd,J=7.57, 1.30 Hz, 1 H), 7.34 - 7.38 (m, 1 H), 7.27 - 7.34 (m, 2 H), 7.18 (dd,J=7.49, 1.07 Hz, 1 H), 7.11 (ddd,J=8.29, 2.56, 0.92 Hz, 1 H), 7.03 (ddd,J=7.79, 1.68, 0.92 Hz, 1 H), 6.71 - 6.73 (m, 1 H), 3.57 (s, 3 H), 3.07 - 3.27 (m, 1 H), 2.07 - 2.34 (m, 1 H), 1.64 - 2.06 (m, 3 H), 1.22 - 1.53 (m, 1 H); MH + 382

[0748]

[0749] Step 4: 1-(1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (146)

[0750] 1-((3-Methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (125 mg, 1 eq) was dissolved in MeOH (1.64 mL, 0.2 M), and a 2 M methylamine solution in MeOH (0.41 mL, 2.5 eq) was added. The mixture was stirred at room temperature for 2 h. After lowering the temperature to 0°C, NaBH4 (6.2 mg, 0.5 eq) was added and stirred at room temperature for 20 min. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (yellow sticky oil, 105 mg, yield 80%).

[0751] 1 H NMR (500 MHz, MeOH-d4) δ 7.59 (dd,J=7.72, 1.15 Hz, 1 H), 7.41 (s, 1 H), 7.29 - 7.34 (m, 1 H), 7.23 - 7.28 (m, 2 H), 7.16 - 7.20 (m, 1 H), 7.07 (ddd,J=8.41, 2.60, 0.92 Hz, 1 H), 6.98 (ddd,J=7.76, 1.72, 0.92 Hz, 1 H), 6.68 (dd,J=2.45, 1.83 Hz, 1 H), 3.60 (d,J=0.76 Hz, 2 H), 3.57 (s, 3 H), 2.39 (s, 3 H), 2.31 - 2.52 (m, 1 H), 2.08 - 2.30 (m, 1 H), 1.70 - 2.06 (m, 3 H), 1.32 - 1.57 (m, 1 H); MH+ 397

[0752]

[0753] Step 5: 1-(1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (147)

[0754] 1-(1-((3-Methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (55 mg, 1 eq) was dissolved in ethyl acetate (1.39 mL, 0.1 M) and cooled to 0°C. 1N HCl in EtOAc (0.17 mL, 1.2 eq) was added at 0°C, and the temperature was increased to room temperature and stirred at room temperature for 1 hour and 30 minutes. The resulting solid was filtered with ethyl acetate to obtain 1-(1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (50 mg of white solid, yield 83%).

[0755] 1 H NMR (500 MHz, MeOH-d4) δ 7.68 (s, 1 H), 7.61 (dd,J=7.57, 1.30 Hz, 1 H), 7.33 - 7.37 (m, 1 H), 7.25 - 7.32 (m, 2 H), 7.20 (dd,J=7.49, 1.22 Hz, 1 H), 7.10 (ddd,J=8.33, 2.60, 0.84 Hz, 1 H), 6.99 (ddd,J=7.79, 1.68, 0.92 Hz, 1 H), 6.69 (dd,J=2.45, 1.83 Hz, 1 H), 4.10 (s, 2 H), 3.57 (s, 3 H), 2.70 (s, 3 H), 2.36 - 2.61 (m, 1 H), 2.12 - 2.35 (m, 1 H), 1.72 - 2.12 (m, 3 H), 1.30 - 1.56 (m, 1 H); MS m / z 397 (MH + - HCl)

[0756]

[0757] [Example 30] 1-(1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (154)

[0758]

[0759] Step 1: 1-((3-hydroxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylic acid (148)

[0760] Methyl 1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (200 mg, 1 eq) was dissolved in DCM (2.43 mL, 0.2 M) and cooled to 0°C. At 0°C, a 1.0 M BBr3 solution in DCM (1.46 mL, 3 eq) was added, warmed to room temperature, and stirred at room temperature for 1 h. After cooling to 0°C and adding distilled water, the reaction was quenched, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((3-hydroxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylic acid (164 mg of dark green sticky oil, yield 87%).

[0761] 1H NMR (500 MHz, MeOH-d4) δ 7.99 (s, 1 H), 7.57 (dd,J=7.64, 1.38 Hz, 1 H), 7.29 (dtd,J=18.03, 7.41, 7.41, 1.53 Hz, 2 H), 7.16 (dd,J=7.34, 1.22 Hz, 1 H), 7.10 - 7.14 (m, 1 H), 6.93 (ddd,J=8.25, 2.45, 0.92 Hz, 1 H), 6.74 (ddd,J=7.83, 1.87, 0.99 Hz, 1 H), 6.70 (t,J=2.06) Hz, 1 H), 2.16 - 2.32 (m, 1 H), 1.87 - 2.06 (m, 3 H), 1.71 - 1.86 (m, 1 H), 1.41 - 1.58 (m, 1 H); MH + 384

[0762]

[0763] Step 2: 3-Methoxypropyl 1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (150)

[0764] 1-((3-Hydroxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylic acid (333 mg, 1 eq) was dissolved in DMF (8.69 mL, 0.1 M), and K2CO3 (240 mg, 2 eq) and 1-bromo-3-methoxypropane (0.39 mL, 4 eq) were added, and the temperature was raised to 60°C. After stirring at 60°C for 50 minutes, the temperature was lowered to 0°C. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by amine column chromatography to obtain 3-methoxypropyl 1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (yellow oil 336 mg, yield 73%).

[0765] 1 H NMR (500 MHz, MeOH-d4) δ 8.01 (s, 1 H), 7.63 (dd,J=7.72, 1.30 Hz, 1 H), 7.25 - 7.38 (m, 3 H), 7.18 (dd,J=7.41, 1.15 Hz, 1 H), 7.10 (ddd,J=8.29, 2.56, 0.92 Hz, 1 H), 7.00 (ddd,J=7.83, 1.80, 0.92 Hz, 1 H), 6.65 - 6.67 (m, 1 H), 4.33 (t,J=6.34 Hz, 2 H), 3.66 - 3.88 (m, 2 H), 3.54 (t,J=6.11 Hz, 2 H), 3.50 (t,J=6.19 Hz, 2 H), 3.36 (s, 6 H), 3.11 - 3.24 (m, 1 H), 2.13 - 2.29 (m, 1 H), 1.86 - 2.07 (m, 6 H), 1.69 - 1.86 (m, 1) H), 1.25 - 1.46 (m, 1 H); MH + 528

[0766]

[0767] Step 3: (1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (151)

[0768] 3-Methoxypropyl 1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (325 mg, 1 eq) was dissolved in THF (3.08 mL, 0.2 M) and the temperature was lowered to 0℃. 1 M DIBAL-H in toluene (1.85 mL, 3 eq) was slowly added and stirred at 0℃ for 30 minutes. The reaction was quenched by adding 1 N HCl aqueous solution, diluted with ethyl acetate, and washed several times with distilled water and a saturated aqueous solution of potassium sodium tartrate. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. After concentrating the filtrate under reduced pressure, (1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol was obtained. The synthesized compound was used in the next reaction without a separate purification process (253 mg of red sticky oil, crude).

[0769] 1 H NMR (500 MHz, MeOH-d4) δ 7.59 (dd,J=7.72, 1.30 Hz, 1 H), 7.37 (s, 1 H), 7.29 - 7.33 (m, 1 H), 7.22 - 7.28 (m, 2 H), 7.18 (dd,J=7.49, 1.22 Hz, 1 H), 7.06 (ddd,J=8.29, 2.56, 0.92 Hz, 1 H), 6.96 - 7.01 (m, 1 H), 6.63 - 6.68 (m, 1 H), 4.47 (d,J=0.76 Hz, 2 H), 3.76 (br s, 2 H), 3.50 (t,J=6.11 Hz, 2 H), 3.36 (s, 3 H), 2.37 - 2.62 (m, 1 H), 2.11 - 2.34 (m, 1 H), 1.88 - 2.09 (m, 4 H), 1.70 - 1.86 (m, 1 H), 1.36 - 1.67 (m, 1 H); MH + 442

[0770]

[0771] Step 4: 1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (152)

[0772] (1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (248 mg, 1 eq) was dissolved in MeCN (2.81 mL, 0.2 M), and molecular sieve 4Å (719 mg) was added and dried. N-Methylmorpholine N-oxide (92 mg, 1.5 eq) and TPAP (29.6 mg, 0.15 eq) were added and stirred at room temperature for 20 min. The molecular sieve 4Å was removed by filtration, washed with EtOAc, and then with distilled water. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (red sticky oil 174 mg, two-step yield 64%).

[0773] 1H NMR (500 MHz, MeOH-d4) δ 9.92 (s, 1 H), 8.24 (s, 1 H), 7.65 (dd,J=7.72, 1.30 Hz, 1 H), 7.26 - 7.38 (m, 3 H), 7.19 (dd,J=7.41, 1.15 Hz, 1 H), 7.11 (ddd,J=8.25, 2.60, 0.92 Hz, 1 H), 7.03 (ddd,J=7.79, 1.83, 0.92 Hz, 1 H), 6.69 - 6.71 (m, 1 H), 3.68 - 3.85 (m, 2 H), 3.50 (t,J=6.11 Hz, 2 H), 3.36 (s, 3 H), 2.10 - 2.32 (m, 1 H), 1.88 - 2.07 (m, 5 H), 1.68 - 1.87 (m, 1 H), 1.26 - 1.49 (m, 1 H); MH + 440

[0774]

[0775] Step 5: 1-(1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (153)

[0776] 1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (165 mg, 1 eq) was dissolved in MeOH (1.88 mL, 0.2 M), and a 2 M methylamine solution in MeOH (0.47 mL, 2.5 eq) was added. The mixture was stirred at room temperature for 1 hour and 30 minutes. After lowering the temperature to 0°C, NaBH4 (7.10 mg, 0.5 eq) was added and stirred at room temperature for 20 minutes. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (yellow sticky oil 148 mg, yield 86%).

[0777] 1 H NMR (500 MHz, MeOH-d4) δ 7.58 (dd,J=7.64, 1.22 Hz, 1 H), 7.40 (s, 1 H), 7.29 - 7.34 (m, 1 H), 7.22 - 7.29 (m, 2 H), 7.18 (dd,J=7.57, 1.15 Hz, 1 H), 7.07 (ddd,J=8.41, 2.60, 0.92 Hz, 1 H), 6.97 - 7.00 (m, 1 H), 6.65 - 6.67 (m, 1 H), 3.77 (br s, 2 H), 3.60 (d,J=0.61 Hz, 2 H), 3.50 (t,J=6.19 Hz, 2 H), 3.36 (s, 3 H), 2.39 (s, 3 H), 2.32 - 2.49 (m, 1 H), 2.10 - 2.31 (m, 1 H), 1.83 - 2.07 (m, 5 H), 1.31 - 1.57 (m, 1 H); MH + 455

[0778]

[0779] Step 6: 1-(1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (154)

[0780] 1-(1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (145 mg, 1 eq) was dissolved in ethyl acetate (3.19 mL, 0.1 M) and cooled to 0°C. 1 N HCl in EtOAc (0.38 mL, 1.2 eq) was added at 0°C, and the temperature was increased to room temperature and stirred at room temperature for 1 h. The resulting solid was filtered with ethyl acetate to obtain 1-(1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (133 mg of white solid, yield 83%).

[0781] 1H NMR (500 MHz, MeOH-d4) δ 7.67 (s, 1 H), 7.61 (dd,J=7.57, 1.30 Hz, 1 H), 7.33 - 7.37 (m, 1 H), 7.31 (td,J=7.37, 1.60 Hz, 1 H), 7.24 - 7.29 (m, 1 H), 7.20 (dd,J=7.41, 1.15 Hz, 1 H), 7.10 (ddd,J=8.29, 2.56, 0.92 Hz, 1 H), 7.00 (ddd,J=7.79, 1.68, 0.92 Hz, 1 H), 6.65 - 6.67 (m, 1 H), 4.10 (s, 2 H), 3.76 (br s, 2 H), 3.50 (t,J=6.11 Hz, 2 H), 3.36 (s, 3 H), 2.70 (s, 3 H), 2.37 - 2.57 (m, 1 H), 2.16 - 2.33 (m, 1 H), 1.83 - 2.09 (m, 5 H), 1.31 - 1.51 (m, 1 H); MS m / z 455 (MH + - HCl)

[0782]

[0783] [Example 31] 1-(1-(Benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (160)

[0784]

[0785] Step 1: Methyl 1-(benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (156)

[0786] Sodium hydride (49.7 mg, 1.5 eq, 1.24 mmol) was dissolved in DMF (2 mL, 0.4 M) and stirred, and methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (200 mg, 1 eq, 0.83 mmol) dissolved in DMF (2 mL, 0.4 M) was added. The mixture was stirred for 1 h at room temperature under nitrogen. Benzo[d][1,3]dioxole-5-sulfonyl chloride (201.2 μL, 1.1 eq, 0.91 mmol) was added and stirred for 10 min at room temperature. After quenching the reaction with H2O, the mixture was extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography (15% EtOAc / Hex) to obtain methyl 1-(benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (orange solid, 207 mg, yield 58%).

[0787] 1 H NMR (500 MHz, MeOH-d4) δ 7.99 (s, 1 H), 7.60 (dd,J=7.57, 1.60 Hz, 1 H), 7.32 (dtd,J=16.10, 7.38, 7.38, 1.53 Hz, 2 H), 7.20 (dd,J=7.41, 1.45 Hz, 1 H), 6.88 (dd,J=8.25, 1.99 Hz, 1 H), 6.71 (d,J=8.25 Hz, 1 H), 6.66 (d,J=1.99 Hz, 1 H), 6.02 (s, 2 H), 3.84 (s, 3 H), 2.07 - 2.37 (m, 2 H), 1.95 - 2.05 (m, 2 H), 1.42 - 1.88 (m, 2 H); MH + 426

[0788]

[0789] Step 2: (1-(Benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (157)

[0790] Methyl 1-(benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (207 mg, 1 eq, 0.49 mmol) was dissolved in THF (1.6 mL, 0.3 M) and stirred at 0°C under nitrogen for 10 minutes. 1 M DIBAL in toluene (1.5 mL, 3 eq, 1.46 mmol) was added and stirred at 0°C for 5 minutes. 1 M aqueous hydrochloric acid solution was added to terminate the reaction, and aqueous sodium potassium tartrate tetrahydrate solution was added. The mixture was extracted twice with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a concentrated residue of (1-(benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (purple oil, 179 mg, yield 93%). MH + 398

[0791]

[0792] Step 3: 1-(Benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (158)

[0793] (1-(Benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol concentrated residue (179 mg, 1 eq, 0.45 mmol) was dissolved in acetonitrile (2.3 mL, 0.2 M), and 600 mg of molecular sieve 4Å was added, followed by 4-methylmorpholine N-oxide (73.5 mg, 2.3 eq, 1.04 mmol) and tetrapropylammonium perruthenate (31.7 mg, 0.2 eq, 0.09 mmol) and stirred at room temperature for 3 hours. After completion of the reaction, Celite ® The mixture was filtered, and the filtrate was quenched with H2O. The mixture was extracted twice with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by normal phase silica gel column chromatography (20% EtOAc / Hex) to obtain 1-(benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (pink solid, 133 mg, yield 75%).

[0794] 1 H NMR (500 MHz, MeOH-d4) δ 9.91 (s, 1 H), 8.20 (s, 1 H), 7.62 (dd,J=7.57, 1.45 Hz, 1 H), 7.28 - 7.39 (m, 2 H), 7.20 (dd,J=7.26, 1.45 Hz, 1 H), 6.87 - 6.96 (m, 1 H), 6.67 - 6.74 (m, 2 H), 6.03 (s, 2 H), 2.02 - 2.40 (m, 2 H), 1.94 - 2.02 (m, 2 H), 1.44 - 1.94 (m, 2 H); MH + 396

[0795]

[0796] Step 4: 1-(1-(Benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (159)

[0797] 1-(Benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (133 mg, 1 eq, 0.37 mmol) was dissolved in methanol (1.9 mL, 0.2 M), 2 M MeNH2 (370 μL, 2 eq, 0.74 mmol) was added, and the mixture was stirred at room temperature for 1 h. After lowering the reaction mixture to 0°C, sodium borohydride (7 mg, 0.5 eq, 0.19 mmol) was added, and the mixture was stirred for 10 min. The reaction was quenched with H2O, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by normal silica gel column chromatography (10% MeOH / DCM) gave 1-(1-(benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (brown gel 65 mg, yield 42%).

[0798] 1 H NMR (500 MHz, MeOH-d4) δ 7.55 (dd,J=7.57, 1.30 Hz, 1 H), 7.37 (s, 1 H), 7.23 - 7.33 (m, 2 H), 7.18 - 7.22 (m, 1 H), 6.87 (dd,J=8.25, 1.99 Hz, 1 H), 6.66 - 6.72 (m, 2 H), 6.01 (s, 2 H), 3.61 (d,J=0.61 Hz, 2 H), 2.40 (s, 3 H), 2.14 - 2.49 (m, 2 H), 1.93 - 2.11 (m, 2 H), 1.45 - 1.74 (m, 2 H); MH + 411

[0799]

[0800] Step 5: 1-(1-(Benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (160)

[0801] 1-(1-(Benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (65 mg, 1 eq, 0.16 mmol) was dissolved in ethyl acetate (0.5 mL, 0.3 M) and stirred at 0°C. 1 M HCl in EtOAc (190 μL, 1.2 eq, 0.19 mmol) was added and stirred for 1 h. Filtration was performed as a filter cake to obtain 1-(1-(benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (40 mg of white solid, yield 56%).

[0802] 1 H NMR (500 MHz, MeOH-d4) δ 7.63 (s, 1 H), 7.56 - 7.59 (m, 1 H), 7.31 (quind,J=7.39, 7.39, 7.39, 7.39, 1.60 Hz, 2 H), 7.19 - 7.23 (m, 1 H), 6.87 (dd,J=8.33, 1.91 Hz, 1 H), 6.71 (d,J=8.25 Hz, 1 H), 6.67 (d,J=1.99 Hz, 1 H), 6.02 (s, 2 H), 4.09 (s, 2 H), 2.70 (s, 3 H), 2.20 - 2.58 (m, 2 H), 1.98 - 2.08 (m, 2 H), 1.44 - 1.98 (m, 2 H); MS m / z 411 (MH + - HCl)

[0803]

[0804] [Example 32] 1-(1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (166)

[0805]

[0806] Step 1: Methyl 1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (162)

[0807] Sodium hydride (49.7 mg, 1.5 eq, 1.24 mmol) was dissolved in DMF (2 mL, 0.4 M) and stirred, and methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (200 mg, 1 eq, 0.83 mmol) dissolved in DMF (2 mL, 0.4 M) was added. The mixture was stirred for 1 h at room temperature under nitrogen. Furan-2-sulfonyl chloride (201.2 μL, 1.1 eq, 0.91 mmol) was added and stirred for 10 min at room temperature. After quenching the reaction with H2O, the mixture was extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography (15% EtOAc / Hex) to obtain methyl 1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (orange solid 207 mg, yield 58%).

[0808] 1 H NMR (500 MHz, MeOH-d4) δ 7.98 (s, 1 H), 7.69 (dd,J=1.76, 0.84 Hz, 1 H), 7.54 - 7.59 (m, 1 H), 7.26 - 7.32 (m, 2 H), 7.18 - 7.22 (m, 1 H), 6.66 (dd,J=3.67, 0.92 Hz, 1 H), 6.43 (dd,J=3.59, 1.76 Hz, 1 H), 3.85 (s, 3 H), 1.96 - 2.50 (m, 2 H), 1.95 - 2.12 (m, 2 H), 1.66 - 1.95 (m, 2H); MH + 372

[0809]

[0810] Step 2: (1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (163)

[0811] Methyl 1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (216 mg, 1 eq, 0.60 mmol) was dissolved in THF (2.0 mL, 0.3 M) and stirred at 0°C under nitrogen for 10 minutes. 1 M DIBAL in toluene (1.5 mL, 3 eq, 1.79 mmol) was added and stirred at 0°C for 5 minutes. 1 M aqueous hydrochloric acid solution was added to terminate the reaction, and aqueous sodium potassium tartrate tetrahydrate solution was added. The mixture was extracted twice with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a concentrated residue of (1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (purple oil, 200 mg, 100%). MH + 344

[0812]

[0813] Step 3: 1-(Furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (164)

[0814] (1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol concentrated residue (222 mg, 1 eq, 0.65 mmol) was dissolved in acetonitrile (3.2 mL, 0.2 M), and 600 mg of molecular sieve 4Å was added, followed by 4-methylmorpholine N-oxide (105.5 mg, 2.3 eq, 1.49 mmol) and tetrapropylammonium perruthenate (45.4 mg, 0.2 eq, 0.13 mmol) and stirred at room temperature for 3 hours. After completion of the reaction, Celite ®The mixture was filtered, and the filtrate was quenched with H2O. The mixture was extracted twice with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by normal phase silica gel column chromatography (20% EtOAc / Hex) to obtain 1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (152 mg of pink solid, yield 69%).

[0815] 1 H NMR (500 MHz, MeOH-d4) δ 9.93 (s, 1 H), 8.21 (s, 1 H), 7.71 (dd,J=1.76, 0.84 Hz, 1 H), 7.57 - 7.61 (m, 1 H), 7.27 - 7.33 (m, 2 H), 7.19 - 7.24 (m, 1 H), 6.70 (dd,J=3.67, 0.92 Hz, 1 H), 6.44 (dd,J=3.67, 1.83 Hz, 1 H), 2.12 - 2.89 (m, 2 H), 2.00 - 2.15 (m, 2 H), 1.60 - 2.00 (m, 2H); MH + 342

[0816]

[0817] Step 4: 1-(1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (165)

[0818] 1-(Furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (152 mg, 1 eq, 0.45 mmol) was dissolved in methanol (2.2 mL, 0.2 M), 2 M MeNH2 (450 μL, 2 eq, 0.89 mmol) was added, and the mixture was stirred at room temperature for 1 h. After lowering the reaction mixture to 0°C, sodium borohydride (8.4 mg, 0.5 eq, 0.22 mmol) was added, and the mixture was stirred for 10 min. The reaction was quenched with H2O, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by normal silica gel column chromatography (10% MeOH / DCM) gave 1-(1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (brown gel 112 mg, yield 71%).

[0819] 1 H NMR (500 MHz, MeOH-d4) δ 7.62 (dd,J=1.83, 0.92 Hz, 1 H), 7.49 - 7.53 (m, 1 H), 7.38 (s, 1 H), 7.18 - 7.29 (m, 3 H), 6.62 (dd,J=3.52, 0.92 Hz, 1 H), 6.43 (dd,J=3.59, 1.76 Hz, 1 H), 3.63 (d,J=0.92 Hz, 2 H), 2.41 (s, 3 H), 2.20 - 2.55 (m, 2 H), 2.01 - 2.11 (m, 2 H), 1.77 - 2.01 (m, 2 H); MH + 357

[0820]

[0821] Step 5: 1-(1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (166)

[0822] 1-(1-(Furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (112 mg, 1 eq, 0.31 mmol) was dissolved in ethyl acetate (0.5 mL, 0.6 M) and stirred at 0°C. 1 M HCl in EtOAc (377 μL, 1.2 eq, 0.38 mmol) was added and stirred for 1 h. The mixture was filtered to obtain 1-(1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (brown solid, 93 mg, yield 75%).

[0823] 1 H NMR (500 MHz, MeOH-d4) δ 7.66 (s, 2 H), 7.52 - 7.55 (m, 1 H), 7.26 - 7.30 (m, 2 H), 7.20 - 7.24 (m, 1 H), 6.65 (dd,J=3.59, 0.84 Hz, 1 H), 6.44 (dd,J=3.67, 1.83 Hz, 1 H), 4.12 (s, 2 H), 2.72 (s, 3 H), 2.23-2.60 (m, 2 H), 2.05-2.12 (m, 2H), 1.70 - 2.04(m, 2H); MS m / z 357 (MH + - HCl)

[0824]

[0825] [Example 33] 1-(1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (172)

[0826]

[0827] Step 1: Methyl 1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (168)

[0828] Methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (250 mg, 1.0 eq) was dissolved in DMF (5 mL), and 60% sodium hydride in mineral oil (103 mg, 1.5 eq) was added at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. 2-Fluorophenylsulfonyl chloride (221 mg, 1.1 eq) was added, the mixture was heated to room temperature, and stirred for 10 minutes. The reaction was terminated by adding distilled water at 0°C, and the organic layer was extracted with distilled water and brine after adding EtOAc. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (yellow solid 408 mg, yield 99%). MH + 400

[0829]

[0830] Step 2: (1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (169)

[0831] Methyl 1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (408 mg, 1.0 eq) was dissolved in THF, and then DIBAL-H in toluene (3 mL, 3.0 eq) was added at 0°C. The reaction was stirred at the same temperature for 30 min. The reaction was terminated by adding 1 N HCl solution at 0°C, and the organic layer was extracted using distilled water and brine after adding EtOAc. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and used for the next reaction without purification. MH + 372

[0832]

[0833] Step 3: 1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (170)

[0834] (1-((2-Fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (379 mg, 1.0 eq) was dissolved in ACN (6 mL), and NMO (166 mg, 2.3 eq) and TPAP (123 mg, 0.15 eq) were added dropwise. After stirring at room temperature for 1 hour, distilled water was added to stop the reaction, and EtOAc was added, and the organic layer was extracted using distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (reddish liquid 300 mg, yield 80%). MH + 370

[0835]

[0836] Step 4: 1-(1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (171)

[0837] 1-((2-Fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (300 mg, 1.0 eq) was dissolved in MeOH (10 mL), and then a solution of MeNH2 (0.12 ml, 1.5 eq) in MeOH was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 h, and then NaBH4 (37 mg, 1.5 eq) was added dropwise and stirred at room temperature for 1 h. The reaction was terminated by adding distilled water at room temperature, and the organic layer was extracted with distilled water and brine after adding EtOAc. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (reddish solid 255 mg, yield 82%).

[0838] 1 H NMR (500 MHz, MeOH-d4) δ 7.55 (dddd,J=8.33, 7.45, 4.93, 1.76 Hz, 1 H), 7.51 (dd,J=7.72, 1.15 Hz, 1 H), 7.44 - 7.47 (m, 1 H), 7.23 - 7.26 (m, 1 H), 7.17 - 7.22 (m, 2 H), 7.15 (ddd,J=10.51, 8.37, 0.99 Hz, 1 H), 7.08 (dd,J=7.57, 1.15 Hz, 1 H), 6.99 (td,J=7.72, 1.07 Hz, 1 H), 3.61 (d,J=0.76 Hz, 2 H), 2.40 (s, 3 H), 2.01 (s, 1 H), 1.98 (br d,J=6.72 Hz, 2 H); MH + 385

[0839]

[0840] Step 5: 1-(1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (172)

[0841] 1-(1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (120 mg, 1.0 eq) was dissolved in EtOAc, and then a solution of HCl in EtOAc (0.5 mL, 1.5 eq) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The entire solution was concentrated under reduced pressure to obtain 1-(1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (110 mg of ivory solid, yield 85%).

[0842] 1 H NMR (500 MHz, MeOH-d4) δ 7.75 - 7.79 (m, 1 H), 7.56 - 7.62 (m, 1 H), 7.53 (dd,J=7.72, 1.15 Hz, 1 H), 7.25 - 7.30 (m, 2 H), 7.22 (td,J=7.49, 1.53 Hz, 1 H), 7.17 (ddd,J=10.55, 8.41, 0.92 Hz, 1 H), 7.08 (dd,J=7.41, 1.15 Hz, 1 H), 7.00 (td,J=7.76, 0.99 Hz, 1 H), 4.57 - 4.62 (m, 1 H), 4.16 (s, 2 H), 2.74 (s, 3 H), 2.17 - 2.58 (m, 1 H), 1.99 - 2.10 (m, 3 H), 1.46 - 1.84 (m, 1 H); MS m / z 385 (MH + - HCl)

[0843]

[0844] [Example 34] 1-(1-(Benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (178)

[0845]

[0846] Step 1: Methyl 1-(benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (174)

[0847] Methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (200 mg, 1.0 eq) was dissolved in DMF (4 mL), and 60% sodium hydride in mineral oil (82 mg, 1.5 eq) was added at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. Benzo[b]thiophene-3-sulfonyl chloride (212 mg, 1.1 eq) was added, and the mixture was heated to room temperature and stirred for 10 minutes. The reaction was terminated by adding distilled water at 0°C, and the organic layer was extracted with distilled water and brine after adding EtOAc. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-(benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (yellow liquid 300 mg, yield 83%). MH + 438

[0848]

[0849] Step 2: (1-(Benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (175)

[0850] Methyl 1-(benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (300 mg, 1.0 eq) was dissolved in THF (5 mL), and then DIBAL-H (2 mL, 3.0 eq) in toluene was added at 0°C. The reaction was stirred at the same temperature for 30 min. The reaction was terminated by adding 1 N HCl solution at 0°C, and the organic layer was extracted using distilled water and brine after adding EtOAc. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and used for the next reaction without purification. MH + 410

[0851]

[0852] Step 3: 1-(Benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (176)

[0853] (1-(Benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (280 mg, 1.0 eq) was dissolved in ACN (6 mL), and NMO (111 mg, 2.3 eq) and TPAP (82.9 mg, 0.15 eq) were added dropwise. After stirring at room temperature for 1 hour, distilled water was added to terminate the reaction, and EtOAc was added to extract the organic layer using distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (purple liquid 270 mg, yield 97%). MH + 408

[0854]

[0855] Step 4: 1-(1-(Benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (177)

[0856] 1-(Benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (270 mg, 1.0 eq) was dissolved in MeOH (10 mL), and then a solution of MeNH2 (0.1 mL, 1.5 eq) in MeOH was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 h, and then NaBH4 (20.89 mg, 0.5 eq) was added dropwise and stirred at room temperature for 1 h. The reaction was terminated by adding distilled water at room temperature, and the organic layer was extracted with distilled water and brine after adding EtOAc. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(1-(benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (purple liquid 128 mg, yield 46%).

[0857] 1 H NMR (500 MHz, MeOH-d4) δ 7.85 (d,J=8.10 Hz, 1 H), 7.83 (s, 1 H), 7.70 (d,J=8.25 Hz, 1 H), 7.63 (dd,J=7.72, 1.15 Hz, 1 H), 7.60 (s, 1 H), 7.36 - 7.41 (m, 1 H), 7.26 - 7.33 (m, 2 H), 7.23 (td,J=7.49, 1.38 Hz, 1 H), 7.05 (dd,J=7.57, 0.99 Hz, 1 H), 3.59 (s, 2 H), 2.01 (s, 1) H), 1.64 - 1.98 (m, 4 H), 0.83 - 1.09 (m, 1 H); MH + 423

[0858]

[0859] Step 5: 1-(1-(Benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (178)

[0860] 1-(1-(Benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (120 mg, 1.0 eq) was dissolved in EtOAc, and then a solution of HCl in EtOAc (0.5 mL, 1.5 eq) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The entire solution was concentrated under reduced pressure to obtain 1-(1-(benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (purple solid, 110 mg, yield 85%).

[0861] 1 H NMR (500 MHz, MeOH-d4) δ 7.87 - 7.92 (m, 3 H), 7.70 (d,J=8.25 Hz, 1 H), 7.66 (dd,J=7.72, 1.15 Hz, 1 H), 7.40 - 7.45 (m, 1 H), 7.32 - 7.36 (m, 2 H), 7.27 (td,J=7.49, 1.38 Hz, 1 H), 7.07 (dd,J=7.49, 0.92 Hz, 1 H), 4.12 (s, 2 H), 2.68 (s, 3 H), 2.43 (br d,J=3.52 Hz, 1 H), 1.65 - 2.04 (m, 4 H); MS m / z 423 (MH + - HCl)

[0862]

[0863] [Example 35] 1-(1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (184)

[0864]

[0865] Step 1: Methyl 1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (180)

[0866] Methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (200 mg, 1.0 eq) was dissolved in DMF (5 mL), and 60% sodium hydride in mineral oil (82.8 mg, 1.5 eq) was added at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. 3,4-Difluorophenylsulfonyl chloride (193.8 mg, 1.1 eq) was added, the temperature was raised to room temperature, and the mixture was stirred for 10 minutes. The reaction was terminated by adding distilled water at 0°C, and the organic layer was extracted with distilled water and brine after adding EtOAc. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (ivory liquid, 300 mg, yield 87%).

[0867] 1 H NMR (500 MHz, MeOH-d4) δ 8.05 (s, 1 H), 7.62 (dd,J=7.57, 1.45 Hz, 1 H), 7.27 - 7.39 (m, 3 H), 7.17 - 7.26 (m, 3 H), 3.85 (s, 3 H), 1.74 - 2.47 (m, 4 H), 1.30 - 1.50 (m, 1 H); MH + 418

[0868]

[0869] Step 2: (1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (181)

[0870] Methyl 1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (300 mg, 1.0 eq) was dissolved in THF (6 mL), and then DIBAL-H (3 mL, 3.0 eq) in toluene was added at 0°C. The reaction mixture was stirred at the same temperature for 30 min. The reaction was terminated by adding 1 N HCl solution at 0°C, and the organic layer was extracted using distilled water and brine after adding EtOAc. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and used for the next reaction without purification. MH + 390

[0871]

[0872] Step 3: 1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (182)

[0873] (1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (290 mg, 1.0 eq) was dissolved in ACN (6 mL), and NMO (158 mg, 2.3 eq) and TPAP (118 mg, 0.15 eq) were added dropwise. After stirring at room temperature for 1 hour, distilled water was added to stop the reaction, and EtOAc was added, and the organic layer was extracted using distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (purple solid, 160 mg, yield 55%).

[0874] 1H NMR (500 MHz, MeOH-d4) δ 9.93 (s, 1 H), 8.26 (s, 1 H), 7.64 (dd,J=7.49, 1.53 Hz, 1 H), 7.21 - 7.41 (m, 8 H), 1.36 - 2.53 (m, 6 H); MH + 388

[0875]

[0876] Step 4: 1-(1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (183)

[0877] 1-((3,4-Difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (160 mg, 1.0 eq) was dissolved in MeOH (10 mL), and then a solution of MeNH2 (0.6 mL, 1.5 eq) in MeOH was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 h, and then NaBH4 (13 mg, 0.5 eq) was added dropwise and stirred at room temperature for 1 h. The reaction was terminated by adding distilled water at room temperature, and the organic layer was extracted with distilled water and brine after adding EtOAc. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (purple liquid 255 mg, yield 82%).

[0878] 1 H NMR (500 MHz, MeOH-d4) δ 7.52 - 7.63 (m, 2 H), 7.13 - 7.38 (m, 6 H), 3.94 - 4.02 (m, 1 H), 2.88 - 2.93 (m, 1 H), 2.62 - 2.66 (m, 2 H), 1.73 - 2.09 (m, 4 H); MH + 403

[0879]

[0880] Step 5: 1-(1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (184)

[0881] 1-(1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (120 mg, 1.0 eq) was dissolved in EtOAc, and then a solution of HCl in EtOAc (0.5 ml, 1.5 eq) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The entire solution was concentrated under reduced pressure to obtain 1-(1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (purple solid, 110 mg, yield 85%).

[0882] 1 H NMR (500 MHz, MeOH-d4) δ 7.71 (s, 1 H), 7.60 (dd,J=7.49, 1.53 Hz, 1 H), 7.29 - 7.39 (m, 3 H), 7.18 - 7.26 (m, 3 H), 4.13 (s, 2 H), 4.08 - 4.11 (m, 1 H), 2.73 (s, 3 H), 1.32 - 2.62 (m, 6 H); MS m / z 403 (MH + - HCl)

[0883]

[0884] [Example 36] 1-(1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (190)

[0885]

[0886] Step 1: Methyl 1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (186)

[0887] Methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (250 mg, 1.0 eq) was dissolved in DMF (5 mL), and 60% sodium hydride in mineral oil (103 mg, 1.5 eq) was added at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. 3-Chloro-4-fluorobenzenesulfonyl chloride (261 mg, 1.5 eq) was added, the mixture was heated to room temperature, and stirred for 10 minutes. The reaction was terminated by adding distilled water at 0°C, and the organic layer was extracted with distilled water and brine after adding EtOAc. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (ivory liquid, 250 mg, yield 56%). MH + 434

[0888]

[0889] Step 2: (1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (187)

[0890] Methyl 1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (250 mg, 1.0 eq) was dissolved in THF (6 mL), and then DIBAL-H (3.0 mL, 3.0 eq) in toluene was added at 0°C. The reaction was stirred at the same temperature for 30 min. The reaction was terminated by adding 1 N HCl solution at 0°C, and the organic layer was extracted using distilled water and brine after adding EtOAc. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and used for the next reaction without purification. MH + 406

[0891]

[0892] Step 3: 1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (188)

[0893] (1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (200 mg, 1.0 eq) was dissolved in ACN (6 mL), and NMO (80.4 mg, 2.3 eq) and TPAP (59.7 mg, 0.15 eq) were added dropwise. After stirring at room temperature for 1 hour, distilled water was added to stop the reaction, and EtOAc was added to extract the organic layer using distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (purple solid 160 mg, yield 55%). MH + 404

[0894]

[0895] Step 4: 1-(1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (189)

[0896] 1-((3-Chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (160 mg, 1.0 eq) was dissolved in MeOH (10 mL), and then a solution of MeNH2 (0.06 mL, 1.5 eq) in MeOH was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 h, and then NaBH4 (12.5 mg, 0.5 eq) was added dropwise and stirred at room temperature for 1 h. The reaction was terminated by adding distilled water at room temperature, and the organic layer was extracted with distilled water and brine after adding EtOAc. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (reddish solid 255 mg, yield 82%).

[0897] 1 H NMR (500 MHz, MeOH-d4) δ 7.58 (dd,J=7.64, 1.38 Hz, 1 H), 7.43 (s, 1 H), 7.16 - 7.41 (m, 6 H), 3.65 (d,J=0.61 Hz, 2 H), 2.42 (s, 3 H), 2.29 (br s, 1 H), 1.55 - 2.09 (m, 4 H), 1.28 - 1.55 (m, 1 H); MH + 419

[0898]

[0899] Step 5: 1-(1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (190)

[0900] 1-(1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (90 mg, 1.0 eq) was dissolved in EtOAc, and then a solution of HCl in EtOAc (0.5 mL, 1.5 eq) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The entire solution was concentrated under reduced pressure to obtain 1-(1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (ivory solid, 110 mg, yield 85%).

[0901] 1 H NMR (500 MHz, MeOH-d4) δ 7.68 (s, 1 H), 7.60 (dd,J=7.49, 1.53 Hz, 1 H), 7.32 - 7.40 (m, 3 H), 7.23 - 7.30 (m, 3 H), 4.11 (s, 2 H), 2.71 (s, 3 H), 2.24 - 2.59 (m, 2 H), 1.86 - 2.12 (m, 4 H), 1.31 - 1.49 (m, 2 H); MS m / z 419 (MH + - HCl)

[0902]

[0903] [Example 37] 1-(1-((3,4-dimethylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (195)

[0904]

[0905] Step 1: Methyl 1-((3,4-dimethylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (192)

[0906] Methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (250 mg, 1.0 eq) was dissolved in THF (5 mL), and 60% sodium hydride in mineral oil (103 mg, 1.5 eq) was added at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. 3,4-Dimethylphenylsulfonyl chloride (233 mg, 1.1 eq) was added, the mixture was heated to room temperature, and stirred for 10 minutes. The reaction was terminated by adding distilled water at 0°C, and the organic layer was extracted with distilled water and brine after adding EtOAc. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((3,4-dimethylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (yellow solid 320 mg, yield 76%). MH + 410

[0907]

[0908] Step 2: (1-((3,4-dimethylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (193)

[0909] Methyl 1-((3,4-dimethylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (320 mg, 1.0 eq) was dissolved in THF, and DIBAL-H (3.0 mL, 3.0 eq) was added at 0°C. The reaction mixture was stirred at the same temperature for 30 min. The reaction was terminated by adding 1 N HCl solution at 0°C, and the organic layer was extracted using distilled water and brine after adding EtOAc. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and used for the next reaction without purification. MH + 382

[0910]

[0911] Step 3: 1-((3,4-dimethylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (194)

[0912] (1-((3,4-Dimethylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (250 mg, 1.0 eq) was dissolved in ACN (6 mL), and NMO (100 mg, 2.3 eq) and TPAP (74 mg, 0.15 eq) were added dropwise. After stirring at room temperature for 1 hour, distilled water was added to stop the reaction, and EtOAc was added to extract the organic layer using distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((3,4-dimethylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (pink solid 120 mg, yield 48%). MH + 380

[0913]

[0914] Step 4: 1-(1-((3,4-dimethylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (195)

[0915] 1-((3,4-Dimethylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (120 mg, 1.0 eq) was dissolved in MeOH (10 mL), and then a solution of MeNH2 (0.05 mL, 1.5 eq) in MeOH was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 h, and then NaBH4 (10 mg, 0.5 eq) was added dropwise and stirred at room temperature for 1 h. The reaction was terminated by adding distilled water at room temperature, and the organic layer was extracted with distilled water and brine after adding EtOAc. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(1-((3,4-dimethylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (yellow solid 86 mg, yield 69%).

[0916] 1 H NMR (500 MHz, DMSO-d6) δ 7.47 (dd,J=7.64, 1.22 Hz, 1 H), 7.29 - 7.33 (m, 1 H), 7.25 - 7.29 (m, 2 H), 7.22 - 7.25 (m, 1 H), 7.19 (d,J=7.95 Hz, 1 H), 7.06 (dd,J=7.95, 2.14 Hz, 1 H), 6.90 (d,J=1.53 Hz, 1 H), 3.49 (s, 2 H), 2.23 (s, 3 H), 2.21 (s, 3 H), 2.06 (s, 3 H), 1.83 - 1.94 (m, 2 H); MH + 395

[0917]

[0918] [Example 38] 1-(1-((6-methoxypyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (200)

[0919]

[0920] Step 1: Methyl 1-((6-methoxypyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (197)

[0921] Methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (300 mg, 1.0 eq) was dissolved in THF (5 mL), and 60% sodium hydride in mineral oil (124 mg, 1.5 eq) was added at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. 6-Methoxypyridine-3-sulfonyl chloride (283 mg, 1.1 eq) was added, the mixture was heated to room temperature, and stirred for 10 minutes. The reaction was terminated by adding distilled water at 0°C, and the organic layer was extracted with distilled water and brine after adding EtOAc. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((6-methoxypyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (475 mg of white solid, yield 93%). MH + 413

[0922]

[0923] Step 2: (1-((6-methoxypyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (198)

[0924] Methyl 1-((6-methoxypyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (475 mg, 1.0 eq) was dissolved in THF (6 mL), and then DIBAL-H (3.0 mL, 3.0 eq) in toluene was added at 0°C. The reaction was stirred at the same temperature for 30 min. The reaction was terminated by adding 1 N HCl solution at 0°C, and the organic layer was extracted using distilled water and brine after adding EtOAc. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and used for the next reaction without purification. MH + 385

[0925]

[0926] Step 3: 1-((6-methoxypyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (199)

[0927] (1-((6-methoxypyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (350 mg, 1.0 eq) was dissolved in ACN (6 mL), and NMO (148 mg, 2.3 eq) and TPAP (110 mg, 0.15 eq) were added dropwise. After stirring at room temperature for 1 hour, distilled water was added to stop the reaction, and EtOAc was added, and the organic layer was extracted using distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((6-methoxypyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (white solid 220 mg, yield 60%). MH + 383

[0928]

[0929] Step 4: 1-(1-((6-methoxypyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (200)

[0930] 1-((6-Methoxypyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (220 mg, 1.0 eq) was dissolved in MeOH (10 mL), and then a solution of MeNH2 (0.1 mL, 1.5 eq) in MeOH was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 h, and then NaBH4 (18 mg, 0.5 eq) was added dropwise and stirred at room temperature for 1 h. The reaction was terminated by adding distilled water at room temperature, and the organic layer was extracted with distilled water and brine after adding EtOAc. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(1-((6-methoxypyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (196 mg of viscous liquid, yield 85%).

[0931] 1 H NMR (500 MHz, DMSO-d6) δ 8.00 - 8.03 (m, 1 H), 7.50 (dd,J=8.86, 2.60 Hz, 1 H), 7.44 - 7.47 (m, 1 H), 7.31 (s, 2 H), 7.25 (s, 2 H), 6.85 (dd,J=8.86, 0.61 Hz, 1 H), 3.86 (s, 3 H), 3.46 (s, 2 H), 2.21 (s, 3 H), 1.88 - 1.94 (m, 2 H); MH + 398

[0932]

[0933] [Example 39] N-((1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methyl)ethanamine (201)

[0934]

[0935] 1-(Pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (100 mg, 1.0 eq) was dissolved in MeOH (10 mL), and then a solution of EtNH2 (0.04 mL, 1.5 eq) in MeOH was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 h, and then NaBH4 (9 mg, 0.5 eq) was added dropwise and stirred at room temperature for 1 h. The reaction was terminated by adding distilled water at room temperature, and the organic layer was extracted with distilled water and brine after adding EtOAc. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain N-((1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methyl)ethanamine (72 mg of viscous liquid, yield 69%).

[0936] 1 H NMR (500 MHz, DMSO-d6) δ 7.53 - 7.61 (m, 2 H), 7.28 - 7.42 (m, 4 H), 7.19 - 7.26 (m, 1 H), 6.89 - 6.94 (m, 1 H), 3.78 - 3.81 (m, 3 H), 3.57 - 3.63 (m, 2 H), 2.54 - 2.59 (m, 2 H), 2.34 - 2.41 (m, 2 H), 2.26 (s, 3 H); MH + 382

[0937]

[0938] [Example 40] 1-(1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (207)

[0939]

[0940] Step 1: Methyl 1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (203)

[0941] Methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (250 mg) was dissolved in DMF (5.2 mL), and 60% sodium hydride in mineral oil (62 mg) was added at 0°C. The reaction mixture was purged with nitrogen and stirred at room temperature for 1 hour. 4-Methoxybenzenesulfonyl chloride (186 μL) was added at 0°C and stirred at room temperature for 1 hour. The reaction was terminated by adding distilled water at 0°C and extracted with EtOAc. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (yellow oil 379 mg, yield 89%).

[0942] 1H NMR (500 MHz, MeOH-d4) δ 7.98 (s, 1 H), 7.59 (dd,J=7.57, 1.30 Hz, 1 H), 7.24 - 7.33 (m, 2 H), 7.18 - 7.23 (m, 2 H), 7.14 (dd,J=7.34, 1.22 Hz, 1 H), 6.76 - 6.81 (m, 2 H), 3.81 (s, 3 H), 3.76 (s, 3 H), 3.09 - 3.23 (m, 1 H), 2.10 - 2.29 (m, 1 H), 1.84 - 2.02 (m, 2 H), 1.67 - 1.82 (m, 1 H), 1.33 - 1.47 (m, 1 H); MH + 412

[0943]

[0944] Step 2: (1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (204)

[0945] Methyl 1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (379 mg) was dissolved in THF (4.6 mL), and 1 M DIBAL-H in toluene (2.8 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched by adding 1 N HCl aqueous solution, and extracted with EtOAc. The extracted organic layer was washed with potassium sodium tartrate aqueous solution, and then Na2SO4 was added. The mixture was dried and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol. The synthesized compound was used in the next reaction without any separate purification process (yellow oil, crude).

[0946] 1H NMR (500 MHz, MeOH-d4) δ 7.54 (dd,J=7.49, 1.38 Hz, 1 H), 7.33 (s, 1 H), 7.17 - 7.29 (m, 4 H), 7.15 (dd,J=7.41, 1.30 Hz, 1 H), 6.75 - 6.80 (m, 2 H), 4.44 (s, 2 H), 3.76 (s, 3 H), 2.33 - 2.57 (m, 1 H), 2.06 - 2.33 (m, 1 H), 1.93 (br d,J=11.62 Hz, 2 H), 1.70 - 1.89 (m, 1 H), 1.39 - 1.69 (m, 1 H); MH + 384

[0947]

[0948] Step 3: 1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (205)

[0949] (1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (350 mg) was dissolved in acetonitrile (4.6 mL), and molecular sieve 4Å (1.2 g) was added and stirred at room temperature. 4-Methylmorpholine N-oxide (150 mg) and tetrapropylammonium perruthenate (48.5 mg) were added to the reaction mixture and stirred at room temperature for 20 minutes. The reaction mixture was filtered through a celite filter. ® The residue was filtered under reduced pressure and washed with EtOAc. The filtrate was diluted with EtOAc and washed with distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (yellow oil 260 mg, yield 74%).

[0950] 1H NMR (500 MHz, MeOH-d4) δ 9.88 (s, 1 H), 8.19 (s, 1 H), 7.61 (dd,J=7.57, 1.45 Hz, 1 H), 7.22 - 7.33 (m, 4 H), 7.15 (dd,J=7.34, 1.22 Hz, 1 H), 6.77 - 6.82 (m, 2 H), 3.76 (s, 3 H), 2.07 - 2.26 (m, 1 H), 1.86 - 2.04 (m, 3 H), 1.69 - 1.86 (m, 1 H), 1.30 - 1.59 (m, 1 H); MH + 382

[0951]

[0952] Step 4: 1-(1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (206)

[0953] 1-((4-Methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (260 mg) was dissolved in MeOH (3.4 mL), 2M MeNH2 in MeOH (0.85 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After cooling the reaction to 0°C, sodium borohydride (13 mg) was slowly added dropwise, and the mixture was stirred at room temperature for 10 minutes. The reaction was terminated by adding distilled water at 0°C, diluted with EtOAc, and washed with distilled water and brine. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (yellow oil 173 mg, yield 64%). MH + 397

[0954]

[0955] Step 5: 1-(1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (207)

[0956] 1-(1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (170.5 mg) was dissolved in EtOAc (4.3 mL), and 1 M HCl in EtOAc (0.65 mL) was added. The reaction mixture was stirred at room temperature for 3 h. The resulting solid was filtered with EtOAc to obtain 1-(1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (white solid 160 mg, yield 86%).

[0957] 1 H NMR (500 MHz, MeOH-d4) δ 7.64 (s, 1 H), 7.54 - 7.59 (m, 1 H), 7.24 - 7.32 (m, 2 H), 7.19 - 7.24 (m, 2 H), 7.17 (dd,J=7.34, 1.38 Hz, 1 H), 6.77 - 6.81 (m, 2 H), 4.06 - 4.09 (m, 2 H), 3.76 (s, 3 H), 2.67 (s, 3 H), 2.12 - 2.56 (m, 2 H), 1.79 - 2.07 (m, 3 H), 1.33 - 1.58 (m, 1) H); MS m / z 397 (MH + - HCl)

[0958]

[0959] [Example 41] 3-((3-((methylamino)methyl)-5,6-dihydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-1(4H)-yl)sulfonyl)phenol hydrochloride (209)

[0960]

[0961] Step 1: 3-((3-((methylamino)methyl)-5,6-dihydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-1(4H)-yl)sulfonyl)phenol (208)

[0962] 1-(1-((3-Methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine was dissolved in DCM (1.01 mL, 0.1 M) and the temperature was lowered to 0℃. At 0℃, a 1.0 M BBr3 solution in DCM (0.3 mL, 3 eq) was added, the temperature was raised to room temperature, and the mixture was stirred at room temperature for 1 hour. The temperature was lowered to 0℃, diluted with MeOH, and distilled water was added to stop the reaction. The mixture was neutralized with 1 N NaOH aqueous solution, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 3-((3-((methylamino)methyl)-5,6-dihydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-1(4H)-yl)sulfonyl)phenol (ivory solid, 37 mg, yield 95%).

[0963] 1 H NMR (500 MHz, MeOH-d4) δ 7.54 (dd,J=7.57, 1.30 Hz, 1 H), 7.47 (s, 1 H), 7.23 - 7.31 (m, 2 H), 7.17 - 7.20 (m, 1 H), 7.07 - 7.12 (m, 1 H), 6.89 - 6.92 (m, 1 H), 6.69 - 6.73 (m, 2 H), 3.77 (s, 2 H), 2.49 (s, 3 H), 2.08 - 2.41 (m, 1 H), 1.73 - 2.07 (m, 4 H), 1.48 - 1.69 (m, 1) H); MH + 383

[0964]

[0965] Step 2: 3-((3-((methylamino)methyl)-5,6-dihydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-1(4H)-yl)sulfonyl)phenol hydrochloride (209)

[0966] 3-((3-((methylamino)methyl)-5,6-dihydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-1(4H)-yl)sulfonyl)phenol (35 mg, 1 eq) was dissolved in ethyl acetate (0.92 mL, 0.1 M) and cooled to 0°C. 1N HCl in EtOAc (0.11 mL, 1.2 eq) was added at 0°C, and the temperature was increased to room temperature and stirred at room temperature for 3 h. The resulting solid was filtered with ethyl acetate to obtain 3-((3-((methylamino)methyl)-5,6-dihydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-1(4H)-yl)sulfonyl)phenol hydrochloride (ivory solid, 34 mg, yield 88%).

[0967] 1 H NMR (500 MHz, MeOH-d4) δ 7.65 (s, 1 H), 7.54 - 7.58 (m, 1 H), 7.30 (quind,J=7.32, 1.60 Hz, 2 H), 7.19 (dd,J=7.34, 1.53 Hz, 1 H), 7.12 (t,J=8.02 Hz, 1 H), 6.93 (ddd,J=8.10, 2.45, 0.92 Hz, 1 H), 6.75 (ddd,J=7.79, 1.83, 0.92 Hz, 1 H), 6.71 (t,J=2.06 Hz, 1 H), 4.09 (s, 2 H), 2.69 (s, 3 H), 2.38 - 2.59 (m, 1 H), 2.17 - 2.36 (m, 1 H), 1.81 - 2.13 (m, 3 H), 1.41 - 1.70 (m, 1 H); MS m / z 383 (MH + - HCl)

[0968]

[0969] [Example 42] N-Methyl-1-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine fumarate (215)

[0970]

[0971] Step 1: Methyl 1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (211)

[0972] Methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (250 mg) was dissolved in THF (5.2 mL), and 60% sodium hydride in mineral oil (62 mg) was added at 0°C. The reaction mixture was purged with nitrogen and stirred at room temperature for 30 minutes. 1-Methyl-1H-imidazole-4-sulfonyl chloride (225 mg) was added, and stirred at room temperature for 16 hours. The reaction was terminated by adding distilled water at 0°C, and extracted with EtOAc. The extracted organic layer was washed with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (white solid 196 mg, yield 49%).

[0973] 1H NMR (500 MHz, DMSO-d6) δ 7.84 (s, 1 H), 7.77 (d,J=0.92 Hz, 1 H), 7.60 (d,J=1.22 Hz, 1 H), 7.55 - 7.58 (m, 1 H), 7.24 - 7.31 (m, 3 H), 3.78 (s, 3 H), 3.55 (s, 3 H), 2.99 - 3.26 (m, 1 H), 2.36 (br s, 1 H), 1.96 - 2.02 (m, 2 H), 1.55 - 1.94 (m, 2 H); MH + 386

[0974]

[0975] Step 2: (1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (212)

[0976] Methyl 1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (189 mg) was dissolved in THF (2.45 mL), and 1 M DIBAL-H in toluene (1.48 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched by adding 1 N HCl aqueous solution, and extracted with EtOAc. The extracted organic layer was washed with potassium sodium tartrate aqueous solution, and then Na2SO4 was added. The mixture was dried and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol. The synthesized compound was used in the next reaction without any separate purification process (clear oil, crude).

[0977] 1H NMR (500 MHz, DMSO-d6) δ 7.68 (d,J=0.92 Hz, 1 H), 7.44 - 7.54 (m, 2 H), 7.16 - 7.24 (m, 3 H), 7.13 (s, 1 H), 4.88 (t,J=5.35 Hz, 1 H), 4.30 (d,J=4.89 Hz, 2 H), 3.53 (s, 3 H), 2.00 - 2.37 (m, 3 H), 1.91 - 1.99 (m, 2 H), 1.71 - 1.90 (m, 1 H); MH + 358

[0978]

[0979] Step 3: 1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (213)

[0980] (1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (175 mg) was dissolved in acetonitrile (2.5 mL), and molecular sieve 4Å (600 mg) was added and stirred at room temperature. 4-Methylmorpholine N-oxide (80 mg) and tetrapropylammonium perruthenate (26 mg) were added to the reaction mixture and stirred at room temperature for 20 minutes. The reaction mixture was filtered through celite. ® The residue was filtered under reduced pressure and washed with EtOAc. The filtrate was diluted with EtOAc and washed with distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (white solid 66 mg, yield 37%).

[0981] 1H NMR (500 MHz, DMSO-d6) δ 9.89 (s, 1 H), 8.21 (s, 1 H), 7.74 (d,J=1.07 Hz, 1 H), 7.55 (d,J=1.22 Hz, 1 H), 7.52 - 7.54 (m, 1 H), 7.23 - 7.28 (m, 2 H), 7.20 - 7.23 (m, 1 H), 3.51 (s, 3 H), 3.32 - 3.33 (m, 1 H), 2.84 - 3.23 (m, 2 H), 1.89 - 2.02 (m, 2 H), 1.44 - 2.39 (m, 2) H); MH + 356

[0982]

[0983] Step 4: N-Methyl-1-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (214)

[0984] 1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (64 mg) was dissolved in MeOH (0.9 mL), 2M MeNH2 in MeOH (0.23 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After cooling the reaction to 0°C, sodium borohydride (3.4 mg) was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction was terminated by adding distilled water at 0°C, diluted with EtOAc, and washed with distilled water and brine. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain N-methyl-1-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (yellow oil 60 mg, yield 90%).

[0985] 1H NMR (500 MHz, DMSO-d6) δ 7.67 (d,J=1.07 Hz, 1 H), 7.48 (dt,J=7.11, 1.18 Hz, 1 H), 7.43 (d,J=1.38 Hz, 1 H), 7.17 - 7.21 (m, 3 H), 7.11 (s, 1 H), 3.52 (s, 3 H), 3.41 - 3.42 (m, 2 H), 2.21 (s, 3 H), 2.03 (br s, 2 H), 1.89 - 1.95 (m, 2 H), 1.70 - 1.89 (m, 2 H); MH + 371

[0986]

[0987] Step 5: N-Methyl-1-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine fumarate (215)

[0988] N-Methyl-1-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (35.6 mg) was dissolved in EtOAc (0.48 mL), and fumaric acid (11.2 mg) was added. The reaction mixture was stirred at room temperature for 16 h. The resulting solid was filtered with EtOAc to obtain N-methyl-1-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine fumarate (white solid 24 mg, yield 49.3%).

[0989] 1H NMR (500 MHz, DMSO-d6) δ 7.72 (d,J=1.22 Hz, 1 H), 7.48 - 7.55 (m, 2 H), 7.44 (s, 1 H), 7.20 - 7.29 (m, 3 H), 6.47 (s, 2 H), 3.84 (s, 2 H), 3.55 (s, 3H), 2.44 (s, 3 H), 2.04 - 2.41 (m, 2 H), 1.95 - 2.04 (m, 3 H), 1.90 (br s, 1 H); MS m / z 371 (MH + - C4H4O4)

[0990]

[0991] [Example 43] N-Methyl-1-(1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (220)

[0992]

[0993] Step 1: Methyl 1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (217)

[0994] Sodium hydride (29.8 mg, 1.5 eq, 1.24 mmol) was dissolved in DMF (2 mL, 0.4 M) and stirred, and methyl 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (200 mg, 1 eq, 0.83 mmol) dissolved in THF (2 mL, 0.4 M) was added. The mixture was stirred for 1 h at room temperature under nitrogen. 6-Methylpyridine-3-sulfonyl chloride (151.8 μL, 1.1 eq, 0.91 mmol) was added and stirred at room temperature for 10 min. After quenching the reaction with H2O, the mixture was extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography (20-50% EtOAc / Hex) to obtain methyl 1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (pink solid, 238 mg, yield 77%).

[0995] 1 H NMR (500 MHz, MeOH-d4) δ 8.21 (d,J=2.29 Hz, 1 H), 8.06 (s, 1 H), 7.59 - 7.64 (m, 2 H), 7.30 - 7.39 (m, 2 H), 7.27 (d,J=8.41 Hz, 1 H), 7.19 (dd,J=7.34, 1.22 Hz, 1 H), 3.85 (s, 3 H), 3.18 - 3.28 (m, 1 H), 2.51 (s, 3 H), 2.17 - 2.31 (m, 1 H), 1.90 - 2.04 (m, 2 H), 1.73 - 1.88 (m, 1 H), 1.28 - 1.41 (m, 1 H); MH + 397

[0996]

[0997] Step 2: (1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (218)

[0998] Methyl 1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (238 mg, 1 eq, 0.60 mmol) was dissolved in THF (3.0 mL, 0.2 M) and stirred at 0°C under nitrogen for 10 minutes. 1 M DIBAL in toluene (1.8 mL, 3 eq, 1.80 mmol) was added and stirred at 0°C for 5 minutes. 1 M hydrochloric acid was added to terminate the reaction, and an aqueous solution of sodium potassium tartrate tetrahydrate was added. The mixture was extracted twice with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a concentrated residue of (1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (yellow oil 234 mg, 101%).

[0999] 1 H NMR (500 MHz, MeOH-d4) δ 8.21 (d,J=2.14 Hz, 1 H), 7.55 - 7.61 (m, 2 H), 7.40 (t,J=0.84 Hz, 1 H), 7.25 - 7.34 (m, 3 H), 7.20 (dd,J=7.41, 1.30 Hz, 1 H), 4.47 (d,J=0.92 Hz, 2 H), 3.32 - 3.35 (m, 1 H), 2.52 (s, 3 H), 2.11 - 2.35 (m, 1 H), 1.92 - 2.08 (m, 2 H), 1.39 - 1.67 (m, 1 H), 1.24 - 1.39 (m, 1 H); MH + 369

[1000]

[1001] Step 3: 1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (219)

[1002] (1-((6-Methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol concentrated residue (234 mg, 1 eq, 0.60 mmol) was dissolved in acetonitrile (3.0 mL, 0.2 M), and 600 mg of molecular sieve 4Å was added, followed by 4-methylmorpholine N-oxide (43 mg, 1.01 eq, 0.61 mmol) and tetrapropylammonium perruthenate (31.6 mg, 0.2 eq, 0.09 mmol) and stirred at room temperature for 3 hours. After completion of the reaction, Celite ® The mixture was filtered, and the filtrate was quenched with H2O. The mixture was extracted twice with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by normal phase silica gel column chromatography (50-100% EtOAc / Hex) to obtain 1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (white solid 135 mg, yield 61%).

[1003] 1 H NMR (500 MHz, MeOH-d4) δ 9.93 (s, 1 H), 8.28 (s, 1 H), 8.25 (d,J=2.29 Hz, 1 H), 7.61 - 7.66 (m, 2 H), 7.32 - 7.39 (m, 2 H), 7.24 - 7.28 (m, 1 H), 7.19 (dd,J=7.41, 1.30 Hz, 1 H), 2.52 (s, 3 H), 2.16 - 2.36 (m, 1 H), 1.94 - 2.08 (m, 3 H), 1.67 - 1.89 (m, 1 H), 1.31 - 1.46 (m, 1 H); MH + 367

[1004]

[1005] Step 4: N-Methyl-1-(1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine (220)

[1006] 1-((6-Methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (135 mg, 1 eq, 0.37 mmol) was dissolved in methanol (1.8 mL, 0.2 M), 2 M MeNH2 (370 μL, 2 eq, 0.74 mmol) was added, and the mixture was stirred at room temperature for 1 h. After lowering the reaction mixture to 0°C, sodium borohydride (7.0 mg, 0.5 eq, 0.18 mmol) was added, and the mixture was stirred for 10 min. The reaction was quenched with H2O, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. N-methyl-1-(1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine was obtained by purification by normal silica gel column chromatography (5-15% MeOH / DCM) (brown gel 116 mg, yield 83%).

[1007] 1 H NMR (500 MHz, MeOH-d4) δ 8.23 ​​(d,J=2.14 Hz, 1 H), 7.56 - 7.60 (m, 2 H), 7.51 (s, 1 H), 7.31 - 7.35 (m, 1 H), 7.29 (td,J=7.41, 1.53 Hz, 1 H), 7.26 (d,J=8.41 Hz, 1 H), 7.21 (dd,J=7.41, 1.30 Hz, 1 H), 3.74 (s, 2 H), 3.35 (s, 1 H), 2.52 (s, 3 H), 2.48 (s, 3 H), 2.15 - 2.35 (m, 1 H), 1.78 - 2.09 (m, 3 H), 1.25 - 1.50 (m, 1 H), 0.78 - 0.99 (m, 1 H); MH + 382

[1008]

[1009] [Example 44] 1-(8-chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (229)

[1010]

[1011]

[1012] Step 1: 2-Chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one oxime (222)

[1013] 2-Chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (500 mg, 1 eq), hydroxylamine HCl (196 mg, 1.1 eq), and sodium acetate (316 mg, 1.5 eq) were dissolved in ethanol / H2O (1:1, 15.57 mL, 0.17 M), heated to 90°C, and stirred for 4 hours. After lowering the temperature to room temperature, ethyl acetate was added to the reaction solution, diluted, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain 2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one oxime. The synthesized compound was used in the following reaction without a separate purification process (530 mg of white solid, crude, 5.26:1 mixture of E / Z isomer).

[1014] 1 H NMR (500 MHz, MeOH-d4) for the major (E)-isomer δ 7.30 (d,J=8.25 Hz, 1 H), 7.20 - 7.23 (m, 1 H), 7.19 (d,J=1.83 Hz, 1 H), 2.71 - 2.75 (m, 2 H), 2.66 - 2.71 (m, 2 H), 1.78 (quin,J=6.57 Hz, 2 H), 1.58 - 1.65 (m, 2 H), Partial 1H NMR for the minor (Z)-isomer δ 7.24 - 7.27 (m, 1 H), 2.38 - 2.43 (m, 2 H), 1.85 - 1.92 (m, 2 H), 1.71 - 1.76 (m, 2 H); MH + 210

[1015]

[1016] Step 2: Methyl 3-(((2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ylidene)amino)oxy)acrylate (223)

[1017] 2-Chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one oxime (538 mg, 1 eq) was dissolved in DMSO (2.57 mL, 1 M), and TEA (0.36 mL, 1 eq) was slowly added at room temperature. Methyl propiolate (0.46 mL, 2 eq) dissolved in DMSO (1.03 mL, 2.5 M) was slowly added, and the mixture was stirred at room temperature for 20 minutes. EtOAc was added to the reaction solution, diluted, and washed several times with distilled water and brine. The extracted organic layer was filtered and purified by filtration using Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 3-(((2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ylidene)amino)oxy)acrylate (yellow sticky oil 688 mg, two-step yield 91%, 73:10:17:0 mixture of (E / Z) / (E / Z) isomer).

[1018] 1H NMR (500 MHz, MeOH-d4) δ for the major (E) / (E)-isomer 8.06 (d,J=12.53 Hz, 1 H), 7.38 - 7.44 (m, 1 H), 7.23 - 7.33 (m, 2H), 5.62 (d,J=12.69 Hz, 1 H), 3.71 (s, 3 H), 2.80 - 2.84 (m, 2 H), 2.72 - 2.80 (m, 2 H), 1.75 - 1.85 (m, 2 H), 1.61 - 1.71 (m, 2 H), Partial 1 H NMR for the minor (E) / (Z)-isomer δ 7.91 (d,J=12.53 Hz, 1 H), 5.47 (d,J=12.53 Hz, 1 H), Partial 1 H NMR for the minor (Z) / (E)-isomer δ 7.52 (d,J=7.34 Hz, 1 H), 4.96 (d,J=7.34 Hz, 1 H); MH + 294

[1019]

[1020] Step 3: Methyl 8-chloro-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (224)

[1021] Methyl 3-(((2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ylidene)amino)oxy)acrylate (686 mg, 1 eq) was dissolved in 1,4-dioxane (23.35 mL, 0.1 M), DBU (1.40 mL, 4 eq) was added, heated to 110°C, and stirred for 17 hours. After lowering the temperature to room temperature, ethyl acetate was added to the reaction solution, diluted, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 8-chloro-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (yellow solid, 405 mg, yield 62%).

[1022] 1 H NMR (500 MHz, MeOH-d4) δ 7.50 (s, 1 H), 7.45 (d,J=8.41 Hz, 1 H), 7.21 (dd,J=8.41, 2.29 Hz, 1 H), 7.18 (d,J=1.99 Hz, 1 H), 3.77 (s, 3 H), 3.07 (t,J=6.88 Hz, 2 H), 2.74 - 2.79 (m, 2 H), 1.96 - 2.05 (m, 2 H); MH + 276

[1023]

[1024] Step 4: Methyl 8-chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (225)

[1025] 60% sodium hydride (33 mg, 1.5 eq) in mineral oil was dissolved in THF (1.36 mL, 0.4 M), then methyl 8-chloro-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (150 mg, 1 eq) dissolved in THF (1.36 mL, 0.4 M) was slowly added and stirred at room temperature for 2 hours. 3-Fluorobenzenesulfonyl chloride (0.08 mL, 1.1 eq) was added and stirred at room temperature for 5 hours. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 8-chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (orange sticky gum 192 mg, yield 81%).

[1026] 1 H NMR (500 MHz, MeOH-d4) δ 8.06 (s, 1 H), 7.59 (d,J=8.41 Hz, 1 H), 7.42 - 7.47 (m, 1 H), 7.35 - 7.41 (m, 2 H), 7.21 - 7.26 (m, 2 H), 7.06 (dt,J=8.18, 2.10 Hz, 1 H), 3.85 (s, 3 H), 3.16 - 3.28 (m, 1 H), 2.15 - 2.33 (m, 1 H), 1.88 - 2.11 (m, 2 H), 1.69 - 1.88 (m, 1 H), 1.26 - 1.43 (m, 1 H); MH + 434

[1027]

[1028] Step 5: (8-chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (226)

[1029] Methyl 8-chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (190 mg, 1 eq) was dissolved in THF (2.19 mL, 0.2 M) and the temperature was lowered to 0℃. 1M DIBAL-H in toluene (1.31 mL, 3 eq) was slowly added and stirred at 0℃ for 20 minutes. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water and a saturated aqueous solution of potassium sodium tartrate. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. After concentrating the filtrate under reduced pressure, (8-chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol was obtained. The synthesized compound was used in the next reaction without a separate purification process (purple sticky oil, 184 mg, crude).

[1030] 1 H NMR (500 MHz, MeOH-d4) δ 7.55 (d,J=8.41 Hz, 1 H), 7.38 - 7.44 (m, 2 H), 7.30 - 7.37 (m, 2 H), 7.24 (d,J=2.29 Hz, 1 H), 7.19 (ddd,J=7.79, 1.68, 1.07 Hz, 1 H), 7.05 (dt,J=8.18, 2.10 Hz, 1 H), 4.47 (d,J=0.92 Hz, 2 H), 2.38 - 2.69 (m, 1 H), 2.10 - 2.37 (m, 1 H), 1.72 - 2.08 (m, 3 H), 1.35 - 1.68 (m, 1 H); MH + 406

[1031]

[1032] Step 6: 8-Chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (227)

[1033] (8-Chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (177 mg, 1 eq) was dissolved in MeCN (2.18 mL, 0.2 M), and molecular sieve 4Å (513 mg) was added and dried. N-Methylmorpholine N-oxide (71 mg, 1.5 eq) and TPAP (23 mg, 0.15 eq) were added and stirred at room temperature for 20 min. The molecular sieve 4Å was removed by filtration, washed with EtOAc, and then with distilled water. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 8-chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (136 mg of pink solid, 76% yield in two steps).

[1034] 1 H NMR (500 MHz, MeOH-d4) δ 9.93 (s, 1 H), 8.28 (s, 1 H), 7.61 (d,J=8.25 Hz, 1 H), 7.42 - 7.48 (m, 1 H), 7.37 - 7.42 (m, 2 H), 7.22 - 7.28 (m, 2 H), 7.12 (dt,J=8.10, 2.14 Hz, 1 H), 2.11 - 2.37 (m, 1 H), 1.66 - 2.09 (m, 4 H), 1.20 - 1.53 (m, 1 H); MH + 404

[1035]

[1036] Step 7: 1-(8-chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (228)

[1037] 8-Chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (128 mg, 1 eq) was dissolved in MeOH (1.58 mL, 0.2 M), and a 2 M methylamine solution in MeOH (0.40 mL, 2.5 eq) was added. The mixture was stirred at room temperature for 1 hour and 30 minutes. After lowering the temperature to 0°C, NaBH4 (6 mg, 0.5 eq) was added and stirred at 0°C for 20 minutes. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-(8-chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (95 mg of transparent sticky oil, yield 71%).

[1038] 1 H NMR (500 MHz, MeOH-d4) δ 7.55 (d,J=8.25 Hz, 1 H), 7.52 (s, 1 H), 7.40 - 7.45 (m, 1 H), 7.32 - 7.39 (m, 2 H), 7.25 (d,J=2.14 Hz, 1 H), 7.19 (dt,J=7.76, 1.32 Hz, 1 H), 7.07 (dt,J=8.14, 2.12 Hz, 1 H), 3.76 (s, 2 H), 2.49 (s, 3 H), 2.38 - 2.57 (m, 1 H), 2.16 - 2.38 (m, 1 H), 1.72 - 2.12 (m, 3 H), 1.30 - 1.56 (m, 1 H); MH + 419

[1039]

[1040] Step 8: 1-(8-chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (229)

[1041] 1-(8-Chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (95 mg, 1 eq) was dissolved in ethyl acetate (1.13 mL, 0.2 M) and cooled to 0°C. 1N HCl in EtOAc (0.25 mL, 1.1 eq) was added at 0°C, and the temperature was increased to room temperature and stirred at room temperature for 3 h. The resulting solid was filtered with ethyl acetate to obtain 1-(8-chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (81 mg of a light pink solid, yield 78%).

[1042] 1 H NMR (500 MHz, MeOH-d4) δ 7.71 (s, 1 H), 7.57 (d,J=8.25 Hz, 1 H), 7.41 - 7.46 (m, 1 H), 7.35 - 7.41 (m, 2 H), 7.27 (d,J=2.29 Hz, 1 H), 7.18 - 7.22 (m, 1 H), 7.08 (dt,J=8.10, 2.14 Hz, 1 H), 4.11 (s, 2 H), 2.71 (s, 3 H), 2.40 - 2.65 (m, 1 H), 2.16 - 2.39 (m, 1 H), 1.80 - 2.15 (m, 3 H), 1.27 - 1.59 (m, 1 H); MS m / z 419 (MH + - HCl)

[1043]

[1044] [Example 45] 1-(8-chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (233)

[1045]

[1046] Step 1: Methyl 8-chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (230)

[1047] 60% sodium hydride (52 mg, 1.5 eq) in mineral oil was dissolved in THF (2.18 mL, 0.4 M), then methyl 8-chloro-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (240 mg, 1 eq) dissolved in THF (2.18 mL, 0.4 M) was slowly added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Pyridine-3-sulfonyl chloride (0.11 mL, 1.1 eq) was added, and the mixture was stirred at room temperature for 4 hours. The reaction was stopped by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4, and then filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 8-chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (orange-brown foam 305 mg, yield 84%).

[1048] 1H NMR (500 MHz, MeOH-d4) δ 8.73 (dd,J=4.81, 1.60 Hz, 1 H), 8.43 (dd,J=2.45, 0.76 Hz, 1 H), 8.10 (s, 1 H), 7.82 (ddd,J=8.18, 2.45, 1.60 Hz, 1 H), 7.61 (d,J=8.41 Hz, 1 H), 7.46 (ddd,J=8.18, 4.89, 0.84 Hz, 1 H), 7.39 (dd,J=8.41, 2.29 Hz, 1 H), 7.24 (d,J=2.29 Hz, 1 H), 3.85 (s, 3 H), 3.14 - 3.27 (m, 1 H), 2.16 - 2.31 (m, 1 H), 1.88 - 2.10 (m, 2 H), 1.69 - 1.87 (m, 1 H), 1.20 - 1.38 (m, 1 H); MH + 417

[1049]

[1050] Step 2: (8-chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (231)

[1051] Methyl 8-chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate (300 mg, 1 eq) was dissolved in THF (3.6 mL, 0.2 M) and the temperature was lowered to 0℃. 1M DIBAL-H in toluene (2.16 mL, 3 eq) was slowly added and stirred at 0℃ for 20 minutes. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water and a saturated aqueous solution of potassium sodium tartrate. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. After concentrating the filtrate under reduced pressure, (8-chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol was obtained. The synthesized compound was used in the next reaction without a separate purification process (yellow foam, 288 mg, crude).

[1052] 1 H NMR (500 MHz, MeOH-d4) δ 8.71 (dd,J=4.89, 1.53 Hz, 1 H), 8.41 (dd,J=2.45, 0.76 Hz, 1 H), 7.76 - 7.79 (m, 1 H), 7.57 (d,J=8.41 Hz, 1 H), 7.42 - 7.46 (m, 2 H), 7.34 (dd,J=8.41, 2.29 Hz, 1 H), 7.24 (d,J=2.29 Hz, 1 H), 4.47 (d,J=0.76 Hz, 2 H), 2.36 - 2.64 (m, 1 H), 2.09 - 2.35 (m, 1 H), 1.68 - 2.08 (m, 3 H), 1.19 - 1.64 (m, 1 H); MH + 389

[1053]

[1054] Step 3: 8-Chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (232)

[1055] (8-Chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol (279 mg, 1 eq) was dissolved in MeCN (3.59 mL, 0.2 M), and molecular sieve 4Å (809 mg) was added and dried. N-Methylmorpholine N-oxide (118 mg, 1.5 eq) and TPAP (38 mg, 0.15 eq) were added and stirred at room temperature for 2 hours. The molecular sieve 4Å was removed by filtration, washed with EtOAc, and then with distilled water. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 8-chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (brown solid, 106 mg, two-step yield, 38%).

[1056] 1 H NMR (500 MHz, MeOH-d4) δ 9.94 (s, 1 H), 8.74 (dd,J=4.89, 1.68 Hz, 1 H), 8.47 (dd,J=2.45, 0.76 Hz, 1 H), 8.32 (s, 1 H), 7.84 (ddd,J=8.18, 2.45, 1.60 Hz, 1 H), 7.63 (d,J=8.41 Hz, 1 H), 7.44 - 7.48 (m, 1 H), 7.39 (dd,J=8.33, 2.22 Hz, 1 H), 7.24 (d,J=2.29 Hz, 1 H), 2.13 - 2.41 (m, 1 H), 1.90 - 2.10 (m, 3 H), 1.68 - 1.89 (m, 1 H), 1.19 - 1.48 (m, 1 H); MH + 387

[1057]

[1058] Step 4: 1-(8-chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (233)

[1059] 8-Chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde (100 mg, 1 eq) was dissolved in MeOH (1.29 mL, 0.2 M), and a 2 M methylamine solution in MeOH (0.32 mL, 2.5 eq) was added. The mixture was stirred at room temperature for 1 hour and 30 minutes. After lowering the temperature to 0°C, NaBH4 (5 mg, 0.5 eq) was added and stirred at 0°C for 20 minutes. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by amine column chromatography to obtain 1-(8-chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (61 mg of transparent sticky oil, yield 58%).

[1060] 1 H NMR (500 MHz, MeOH-d4) δ 8.71 (dd,J=4.81, 1.60 Hz, 1 H), 8.42 (dd,J=2.45, 0.61 Hz, 1 H), 7.76 - 7.82 (m, 1 H), 7.56 (d,J=8.25 Hz, 1 H), 7.42 - 7.49 (m, 2 H), 7.35 (dd,J=8.33, 2.22 Hz, 1 H), 7.25 (d,J=2.29 Hz, 1 H), 3.61 (s, 2 H), 2.39 (s, 3 H), 2.36 - 2.63 (m, 1 H), 2.09 - 2.35 (m, 1 H), 1.74 - 2.09 (m, 3 H), 1.20 - 1.48 (m, 1 H); MH + 402

[1061]

[1062] [Example 46] 1-(1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (243)

[1063]

[1064] Step 1: 7,8,9,10-Tetrahydrobenzo[8]annulen-5(6H)-one (235)

[1065] 6-Phenylhexanoic acid (3 g, 1 eq) was dissolved in DCM (260 mL, 0.06 M) and the temperature was lowered to 0°C. Oxalyl chloride (2.68 mL, 2 eq) was added at 0°C and the temperature was raised to room temperature. The mixture was stirred at room temperature for 22 h and then concentrated under reduced pressure. The reaction solution was dissolved in DCM (260 mL, 0.06 M), AlCl3 (8.32 g, 4 eq) was added, and the mixture was stirred at room temperature for 40 min. The reaction was quenched with a saturated aqueous NH4Cl solution, diluted with methylene chloride, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 7,8,9,10-tetrahydrobenzo[8]annulene-5(6H)-one (yellow oil 498 mg, yield 18%).

[1066] 1 H NMR (500 MHz, MeOH-d4) δ 7.59 (dd,J=7.73, 1.43 Hz, 1 H), 7.41 - 7.45 (m, 1 H), 7.29 (td,J=7.45, 1.15 Hz, 1 H), 7.25 (d,J=7.45 Hz, 1 H), 3.04 - 3.08 (m, 2 H), 2.91 - 2.95 (m, 2 H), 1.78 - 1.86 (m, 4 H), 1.49 - 1.55 (m, 2 H); MH + 175

[1067]

[1068] Step 2: 7,8,9,10-Tetrahydrobenzo[8]annulen-5(6H)-one oxime (236)

[1069] 7,8,9,10-Tetrahydrobenzo[8]annulene-5(6H)-one (490 mg, 1 eq), hydroxylamine HCl (234 mg, 1.1 eq), and sodium acetate (376 mg, 1.5 eq) were dissolved in ethanol / H2O (1:1, 18.54 mL, 0.17 M), heated to 90°C, and stirred for 4 hours. After lowering the temperature to room temperature, ethyl acetate was added to the reaction solution, diluted, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain 7,8,9,10-tetrahydrobenzo[8]annulene-5(6H)-one oxime. The synthesized compound was used in the next reaction without a separate purification process (yellow sticky oil 578 mg, crude).

[1070] 1 H NMR (500 MHz, MeOH-d4) for the major (E)-isomer δ 7.28 - 7.32 (m, 1 H), 7.17 - 7.24 (m, 2 H), 7.08 (d,J=8.02 Hz, 1 H), 2.75 - 2.79 (m, 2 H), 2.69 - 2.73 (m, 2 H), 1.69 - 1.75 (m, 2 H), 1.50 - 1.59 (m, 4 H), Partial 1 H NMR for the minor (Z)-isomer δ 6.96 (dd,J=7.16, 1.43 Hz, 1 H); MH + 190

[1071]

[1072] Step 3: Methyl 3-(((7,8,9,10-tetrahydrobenzo[8]annulene-5(6H)-ylidene)amino)oxy)acrylate (237)

[1073] 7,8,9,10-Tetrahydrobenzo[8]annulene-5(6H)-one oxime (578 mg, 1 eq) was dissolved in DMSO (3.05 mL, 1 M), and TEA (0.43 mL, 1 eq) was slowly added at room temperature. Methyl propiolate (0.54 mL, 2 eq) dissolved in DMSO (1.22 mL, 2.5 M) was slowly added, and the mixture was stirred at room temperature for 20 min. MC was added to the reaction solution, diluted, and washed several times with distilled water and then brine. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 3-(((7,8,9,10-tetrahydrobenzo[8]annulene-5(6H)-ylidene)amino)oxy)acrylate (yellow oil 640 mg, two-step yield 76%).

[1074] 1 H NMR (500 MHz, MeOH-d4) δ for the major (E) / (E)-isomer 8.04 (d,J=12.60 Hz, 1 H), 7.35 - 7.39 (m, 1 H), 7.22 - 7.28 (m, 2 H), 7.15 (dd,J=8.02, 1.15 Hz, 1 H), 5.57 (d,J=12.60 Hz, 1 H), 3.70 (s, 3 H), 2.83 - 2.88 (m, 2 H), 2.72 - 2.76 (m, 2 H), 1.71 - 1.77 (m, 2 H), 1.48 - 1.65 (m, 4 H), Partial 1 H NMR for the minor (E) / (Z)-isomer δ 7.86 (d,J=12.60 Hz, 1 H), 5.42 (d,J=12.60 Hz, 1 H), Partial 1 H NMR for the minor (Z) / (E)-isomer δ 7.47 (d,J=7.45 Hz, 1 H), 4.93 (d,J=7.45 Hz, 1 H); MH + 274

[1075]

[1076] Step 4: Methyl 4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carboxylate (238)

[1077] Methyl 3-(((7,8,9,10-tetrahydrobenzo[8]annulene-5(6H)-ylidene)amino)oxy)acrylate (600 mg, 1 eq) was dissolved in 1,4-dioxane (21.95 mL, 0.1 M), DBU (1.31 mL, 4 eq) was added, heated to 110°C, and stirred for 18 hours. After lowering the temperature to room temperature, ethyl acetate was added to the reaction solution, diluted, and washed several times with distilled water and then brine. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carboxylate (yellow solid, 320 mg, yield 55%).

[1078] 1 H NMR (500 MHz, MeOH-d4) δ 7.45 (s, 1 H), 7.30 - 7.32 (m, 1 H), 7.25 (dt,J=6.16, 2.94 Hz, 2 H), 7.19 - 7.22 (m, 1 H), 3.77 (s, 3 H), 2.90 (br s, 2 H), 2.73 (t,J=6.01 Hz, 2 H), 1.69 - 1.92 (m, 2 H), 1.62 (br s, 2 H); MH + 256

[1079]

[1080] Step 5: Methyl 1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carboxylate (239)

[1081] 60% sodium hydride (25.85 mg, 1.5 eq) in mineral oil was dissolved in DMF (1.08 mL, 0.4 M), then methyl 4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carboxylate (110 mg, 1 eq) dissolved in DMF (1.08 mL, 0.4 M) was slowly added, and the mixture was stirred at room temperature for 40 minutes. 3-Fluorobenzenesulfonyl chloride (0.06 mL, 1.1 eq) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction was quenched by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carboxylate (yellow sticky oil, 151 mg, yield 84%).

[1082] 1 H NMR (500 MHz, MeOH-d4) δ 8.09 (s, 1 H), 7.46 - 7.49 (m, 1 H), 7.38 - 7.42 (m, 2 H), 7.34 - 7.38 (m, 1 H), 7.30 (td,J=7.59, 1.43 Hz, 1 H), 7.15 - 7.19 (m, 1 H), 7.13 (d,J=7.45 Hz, 1 H), 6.85 (dt,J=8.02, 2.00 Hz, 1 H), 3.85 (s, 3 H), 3.15 - 3.21 (m, 1 H), 2.19 (dd,J=12.60, 8.02 Hz, 1 H), 1.82 - 1.89 (m, 1 H), 1.69 - 1.75 (m, 1 H), 1.66 (dd,J=13.75, 10.88 Hz, 1 H), 1.14 - 1.24 (m, 2 H), 1.06 - 1.14 (m, 1 H); MH + 414

[1083]

[1084] Step 6: (1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)methanol (240)

[1085] Methyl 1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carboxylate (150 mg, 1 eq) was dissolved in THF (1.81 mL, 0.2 M) and the temperature was lowered to 0℃. 1M DIBAL-H in toluene (1.09 mL, 3 eq) was slowly added and stirred at 0℃ for 20 minutes. The reaction was quenched by adding 1N HCl aqueous solution, diluted with ethyl acetate, and washed several times with distilled water and a saturated aqueous solution of potassium sodium tartrate. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. After concentrating the filtrate under reduced pressure, (1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)methanol was obtained. The synthesized compound was used in the next reaction without a separate purification process (145 mg of orange to yellow oil, crude).

[1086] 1 H NMR (500 MHz, MeOH-d4) δ 7.42 - 7.45 (m, 2 H), 7.30 - 7.42 (m, 3 H), 7.25 (td,J=7.45, 1.15 Hz, 1 H), 7.11 - 7.16 (m, 2 H), 6.86 (dt,J=8.16, 2.22 Hz, 1 H), 4.50 (d,J=1.72 Hz, 2 H), 2.63 (dd,J=14.89, 7.45 Hz, 1 H), 2.24 (dd,J=11.17, 7.73 Hz, 1 H), 1.82 - 1.88 (m, 1 H), 1.74 - 1.81 (m, 1 H), 1.61 - 1.69 (m, 1 H), 1.13 - 1.32 (m, 3 H); MH + 386

[1087]

[1088] Step 7: 1-((3-Fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carbaldehyde (241)

[1089] (1-((3-Fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)methanol (140 mg, 1 eq) was dissolved in MeCN (1.82 mL, 0.2 M), and molecular sieve 4Å (406 mg) was added and dried. N-Methylmorpholine N-oxide (59.52 mg, 1.5 eq) and TPAP (19.2 mg, 0.15 eq) were added and stirred at room temperature for 20 min. Celite ® The organic layer was filtered and washed with EtOAc, then distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carbaldehyde (red sticky oil 105 mg, two-step yield 75%).

[1090] 1 H NMR (500 MHz, MeOH-d4) δ 9.94 (s, 1 H), 8.30 (s, 1 H), 7.49 (dd,J=7.73, 1.43 Hz, 1 H), 7.35 - 7.45 (m, 3 H), 7.28 - 7.33 (m, 1 H), 7.17 - 7.21 (m, 1 H), 7.13 (d,J=6.87 Hz, 1 H), 6.90 (dt,J=8.02, 2.00 Hz, 1 H), 3.21 (dd,J=13.75, 8.59 Hz, 1 H), 2.19 (dd,J=12.31, 7.73 Hz, 1 H), 1.81 - 1.89 (m, 1 H), 1.67 - 1.76 (m, 2 H), 1.09 - 1.27 (m, 3 H); MH + 384

[1091]

[1092] Step 8: 1-(1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (242)

[1093] 1-((3-Fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carbaldehyde (100 mg, 1 eq) was dissolved in MeOH (1.3 mL, 0.2 M), and 2 M methylamine solution in MeOH (0.32 mL, 2.5 eq) was added and stirred at room temperature for 50 min. After lowering the temperature to 0°C, NaBH4 (4.93 mg, 0.5 eq) was added and stirred at room temperature for 20 min. The reaction was terminated by adding distilled water, diluted with ethyl acetate, and washed several times with distilled water. The extracted organic layer was purified by adding Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain 1-(1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)-N-methylmethanamine. The synthesized compound was used in the next reaction without a separate purification process (104 mg of orange sticky oil, crude).

[1094] 1H NMR (500 MHz, MeOH-d4) δ 7.46 (s, 1 H), 7.43 (dd,J=7.73, 1.43 Hz, 1 H), 7.30 - 7.41 (m, 3 H), 7.23 - 7.28 (m, 1 H), 7.12 - 7.16 (m, 2 H), 6.87 (dt,J=8.45, 2.08 Hz, 1 H), 3.62 (s, 2 H), 2.55 (dd,J=14.89, 7.45 Hz, 1 H), 2.47 (s, 3 H), 2.24 (dd,J=11.74, 7.73 Hz, 1 H), 1.76 - 1.88 (m, 2 H), 1.66 (ddd,J=13.32, 8.45, 4.58 Hz, 1 H), 1.18 - 1.31 (m, 2 H), 1.04 - 1.15 (m, 1 H); MH + 399

[1095]

[1096] Step 9: 1-(1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (243)

[1097] 1-(1-((3-Fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)-N-methylmethanamine (100 mg, 1 eq) was dissolved in ethyl acetate (2.51 mL, 0.1 M) and cooled to 0°C. 1 M HCl in EtOAc (0.5 mL, 2.0 eq) was added at 0°C, and the temperature was increased to room temperature and stirred at room temperature for 1 h. The resulting solid was filtered with ethyl acetate to obtain 1-(1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride (70 mg of white solid, yield 64%).

[1098] 1H NMR (500 MHz, MeOH-d4) δ 7.73 (s, 1 H), 7.43 - 7.46 (m, 1 H), 7.34 - 7.43 (m, 3 H), 7.27 - 7.31 (m, 1 H), 7.13 (dd,J=11.46, 7.45 Hz, 2 H), 6.88 (dt,J=8.02, 2.00 Hz, 1 H), 4.07 - 4.14 (m, 2 H), 2.77 (s, 3 H), 2.63 (dd,J=15.18, 7.73 Hz, 1 H), 2.23 (dd,J=12.60, 6.87 Hz, 1 H), 1.83 - 1.92 (m, 2 H), 1.68 - 1.76 (m, 1 H), 1.06 - 1.31 (m, 3 H); MS m / z 399 (MH + - HCl)

[1099]

[1100] [Example 47] N-Methyl-1-(1-(pyridin-3-ylsulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)methanamine dihydrochloride (248)

[1101]

[1102] Step 1: Methyl 1-(pyridin-3-ylsulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carboxylate (244)

[1103] 60% sodium hydride (44.7 mg, 1.5 eq) in mineral oil was dissolved in DMF (1.86 mL, 0.4 M), then methyl 4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carboxylate (190 mg, 1 eq) dissolved in DMF (1.86 mL, 0.4 M) was slowly added and stirred at room temperature for 1 hour. Pyridine-3-sulfonyl chloride (0.098 mL, 1.1 eq) was added and stirred at room temperature for 1 hour. Then, pyridine-3-sulfonyl chloride (0.044 mL, 0.5 eq) was additionally added and stirred at room temperature for 20 minutes. Distilled water was added to quench the reaction, ethyl acetate was added to dilute, and the mixture was washed several times with distilled water. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 1-(pyridin-3-ylsulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carboxylate (yellow sticky gum 230 mg, yield 77%).

[1104] 1 H NMR (500 MHz, MeOH-d4) δ 8.71 (dd,J=4.87, 1.43 Hz, 1 H), 8.26 (d,J=2.29 Hz, 1 H), 8.13 (s, 1 H), 7.65 - 7.72 (m, 1 H), 7.49 (d,J=7.45 Hz, 1 H), 7.37 - 7.43 (m, 2 H), 7.31 (td,J=7.45, 1.15 Hz, 1 H), 7.12 (d,J=7.45 Hz, 1 H), 3.85 (s, 3 H), 3.19 (dd,J=13.75, 8.02 Hz, 1 H), 2.15 (dd,J=13.17, 8.02 Hz, 1 H), 1.81 - 1.92 (m, 1 H), 1.62 - 1.75 (m, 2 H), 1.10 - 1.25 (m, 2 H), 0.98 - 1.07 (m, 1 H); MH + 397

[1105]

[1106] Step 2: (1-(pyridin-3-ylsulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)methanol (245)

[1107] Methyl 1-(pyridin-3-ylsulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carboxylate (210 mg, 1 eq) was dissolved in THF (2.65 mL, 0.2 M) and the temperature was lowered to 0℃. 1M DIBAL-H in toluene (1.59 mL, 3 eq) was slowly added and stirred at 0℃ for 20 minutes. The reaction was quenched by adding 1N HCl aqueous solution, diluted with ethyl acetate, and washed several times with distilled water and a saturated aqueous solution of potassium sodium tartrate. The extracted organic layer was dried over Na2SO4 and filtered under reduced pressure. After concentrating the filtrate under reduced pressure, (1-(pyridin-3-ylsulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)methanol was obtained. The synthesized compound was used in the next reaction without a separate purification process (218 mg of yellow sticky oil, crude).

[1108] 1H NMR (500 MHz, MeOH-d4) δ 8.66 - 8.71 (m, 1 H), 8.26 (d,J=2.29 Hz, 1 H), 7.63 - 7.68 (m, 1 H), 7.47 (s, 1 H), 7.45 (dd,J=7.73, 1.43 Hz, 1 H), 7.39 - 7.43 (m, 1 H), 7.37 (td,J=7.45, 1.15 Hz, 1 H), 7.27 (td,J=7.45, 1.15 Hz, 1 H), 7.14 (dd,J=7.45, 1.15 Hz, 1 H), 4.50 (d,J=2.29 Hz, 2 H), 2.63 (dd,J=14.61, 8.31 Hz, 1 H), 2.18 - 2.24 (m, 1 H), 1.74 - 1.88 (m, 2 H), 1.60 - 1.68 (m, 1 H), 1.12 - 1.26 (m, 3 H); MH + 369

[1109]

[1110] Step 3: 1-(Pyridin-3-ylsulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrole-3-carbaldehyde (246)

[1111] (1-(Pyridin-3-ylsulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)methanol (195 mg, 1 eq) was dissolved in MeCN (2.65 mL, 0.2 M), and molecular sieve 4Å (566 mg) was added and dried. N-Methylmorpholine N-oxide (86.7 mg, 1.5 eq) and TPAP (27.9 mg, 0.15 eq) were added and stirred at room temperature for 20 minutes. Celite ® The organic layer was filtered and washed with EtOAc, then distilled water and brine. The extracted organic layer was treated with Na2SO4. After drying, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatogra...

Claims

1. A compound represented by the following chemical formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof: (I) Here X 1 and X 2 are each independently N or C; Y is O, S, C 1-4 Alkylene, C 1-3 Alkyleneoxy, C 1-3 Alkylenethiol, oxyC 1-3 Alkylene, or thioC 1-3 It is alkylene; L is sulfonyl, C 1-6 Alkylene, or C 1-6 It is alkylenesulfonyl; R 1 Silver C 6-15 Aryl, C 3-15 Cycloalkyl, 5-15 membered heteroaryl, or 3-15 membered heterocycloalkyl, wherein aryl, heteroaryl and heterocycloalkyl are each independently hydroxy, halogen, cyano, C 1-10 Alkyl, haloC 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkoxy-C 1-10 wherein said heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S and O, wherein said heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S and O; R 2 is H, hydroxy, halogen, cyano, C 1-10 Alkyl, haloC 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkoxy-C 1-10 alkoxy, or acetyl; A is C 1-6 Alkylene, C 1-6 Alkylenecarbonyl, or carbonyl; B is H, hydroxy, C 1-10 Alkoxy, or C 1-10 It is alkylamino; Z 1 , Z 2 and Z 3 are each independently H, hydroxy, halogen, cyano, C 1-10 Alkyl, haloC 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkoxy-C 1-10 Alkoxy, or acetyl.

2. In paragraph 1, The residue of the above chemical formula (I) Is , , or and; X 1 and X 2 are each independently N or C; Y' is O or S; A compound, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is an integer from 1 to 3.

3. In paragraph 1, X 1 and X 2 are each independently N or C; Y is O, C 2-4 Alkylene, C 1-3 Alkyleneoxy, or oxyC 1-3 It is alkylene; L is sulfonyl, C 1-6 Alkylene, or C 1-6 It is alkylenesulfonyl; R 1 Silver C 6-12 Aryl, C 3-12 Cycloalkyl, 5-12 membered heteroaryl, or 3-12 membered heterocycloalkyl, wherein aryl, heteroaryl and heterocycloalkyl are each independently hydroxy, halogen, cyano, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 wherein said heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S and O, wherein said heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S and O; R 2 is H or halogen; A is C 1-6 alkylene or carbonyl; B is H, hydroxy, C 1-6 Alkoxy, or C 1-6 It is alkylamino; Z 1 , Z 2 and Z 3 are each independently H, hydroxy, halogen, C 1-6 Alkyl, or C 1-6 An alkoxy compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

4. In paragraph 1, R 1 silver , , , , , , , or And, M is independently CH or N, and at least one M is N; Q is independently NH, S, or O; R A are each independently hydroxy, halogen, cyano, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Selected from the group consisting of alkoxy and acetyl; A compound, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is an integer from 0 to 3.

5. In paragraph 1, X 1 and X 2 One of these is N and the other is C; Y is O, C 2-4 alkylene, oxymethylene, or methyleneoxy; L is sulfonyl or methylene; R 1 is phenyl, 5-12 membered heteroaryl, or 5-12 membered heterocycloalkyl, wherein phenyl, heteroaryl and heterocycloalkyl are each independently hydroxy, halogen, cyano, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 wherein said heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S and O, wherein said heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S and O; R 2 is H or halogen; A is methylene or carbonyl; B is H, hydroxy, methoxy, methylamino, or ethylamino; Z 1 Silver H, Hydroxy, Halogen, C 1-6 Alkyl, or C 1-6 It is alkoxy; Z 2 and Z 3 are each independently H, hydroxy, or C 1-6 An alkoxy compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

6. In paragraph 1, X 1 and X 2 One of these is N and the other is C; Y is O, C 2-4 alkylene, oxymethylene, or methyleneoxy; L is sulfonyl or methylene; R 1 is phenyl, pyridyl, imidazolyl, furanyl, benzodioxolyl, dihydrobenzodioxinyl, benzothiophenyl, or indolyl, wherein phenyl, pyridyl, imidazolyl, furanyl, benzodioxolyl, dihydrobenzodioxinyl, benzothiophenyl, and indolyl each independently have or do not have one or more substituents selected from the group consisting of hydroxy, halogen, cyano, methyl, halomethyl, methoxy, methoxypropoxy, and acetyl; R 2 is H or halogen; A is methylene or carbonyl; B is H, hydroxy, methoxy, methylamino, or ethylamino; Z 1 is H, hydroxy, halogen, ethyl, or methoxy; Z 2 and Z 3 are each independently H, hydroxy, or methoxy, a compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

7. In paragraph 1, The residue -AB of the above chemical formula (I) is , , , , , , or A compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

8. In paragraph 1, The residue of the above chemical formula (I) Is , , , , , or A compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

9. In paragraph 1, R 1 silver , , , , , , , , , , , , , , , , , , , , , , , , , or A compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

10. In paragraph 1, A compound selected from the group consisting of: or a pharmaceutically acceptable salt or stereoisomer thereof; 1> 1-(1-((3-fluorophenyl)sulfonyl)-1H-benzofuro[3,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 2> 1-(1-((3-fluorophenyl)sulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 3> N-methyl-1-(1-(phenylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine hydrochloride; 4> N-methyl-1-(1-tosyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine hydrochloride; 5> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)methanamine dihydrochloride; 6> 1-(1-Benzyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 7> 1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4-dihydrochromeno[4,3-b]pyrrole-3-carboxamide; 8> 1-(1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine hydrochloride; 9> 1-((3-fluorophenyl)sulfonyl)-3-(methoxymethyl)-4,5-dihydro-1H-benzo[g]indole; 10> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)methanamine dihydrochloride; 11> 1-(7-ethyl-1-((3-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine hydrochloride; 12> 1-(1-((3-fluorophenyl)sulfonyl)-7-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine; 13> 1-((3-fluorophenyl)sulfonyl)-3-((methylamino)methyl)-4,5-dihydro-1H-benzo[g]indol-7-ol; 14> 1-(1-((3-fluorophenyl)sulfonyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine; 15> 1-((3-fluorophenyl)sulfonyl)-3-((methylamino)methyl)-4,5-dihydro-1H-benzo[g]indol-8-ol; 16> 1-(1-((3-fluorophenyl)sulfonyl)-6-methoxy-4,5-dihydro-1H-benzo[g]indol-3-yl)-N-methylmethanamine; 17> 1-(1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 18> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine; 19> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine fumarate; 20> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine dihydrochloride; 21> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine 2-hydroxysuccinate; 22> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine 2,3-dihydroxysuccinate; 23> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine difumarate; 24> N-Methyl-1-(1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine hydrochloride; 25> 1-(1-((3-chlorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 26> 1-(1-((4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 27> N-methyl-1-(1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine; 28> 1-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 29> 1-(1-((3-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 30> 1-(1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 31> 1-(1-(Benzo[d][1,3]dioxol-5-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 32> 1-(1-(furan-2-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 33> 1-(1-((2-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 34> 1-(1-(Benzo[b]thiophene-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 35> 1-(1-((3,4-difluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 36> 1-(1-((3-chloro-4-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 37> 1-(1-((3,4-dimethylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine; 38> 1-(1-((6-methoxypyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine; 39> N-((1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methyl)ethanamine; 40> 1-(1-((4-methoxyphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 41> 3-((3-((methylamino)methyl)-5,6-dihydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-1(4H)-yl)sulfonyl)phenol hydrochloride; 42> N-Methyl-1-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine fumarate; 43> N-methyl-1-(1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanamine; 44> 1-(8-chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 45> 1-(8-chloro-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine; 46> 1-(1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 47> N-methyl-1-(1-(pyridin-3-ylsulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)methanamine dihydrochloride; 48> 1-(1-((3-methoxyphenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 49> 3-((3-((methylamino)methyl)-4,5,6,7-tetrahydro-1H-benzo[7,8]cycloocta[1,2-b]pyrrol-1-yl)sulfonyl)phenol hydrochloride; 50> 1-(1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)-N-methylmethanamine hydrochloride; 51> 1-(1-((3-fluorophenyl)sulfonyl)-6,7-dihydro-5H-benzo[c]pyrrolo[1,2-a]azepin-3-yl)-N-methylmethanamine hydrochloride; 52> N-Methyl-1-(1-(pyridin-2-ylsulfonyl)-6,7-dihydro-5H-benzo[c]pyrrolo[1,2-a]azepin-3-yl)methanamine dihydrochloride; 53> 2-Chloro-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carbaldehyde; 54> Methyl 1-((3-cyanophenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate; 55> Methyl 1-((3-acetylphenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrole-3-carboxylate; and 56> (1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-b]pyrrol-3-yl)methanol.

11. A pharmaceutical composition for treating or preventing a disease related to gastric acid secretion, comprising a compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, as an active ingredient.

12. In paragraph 11, Diseases related to the above gastric acid secretion are: A pharmaceutical composition selected from the group consisting of gastrointestinal diseases, dyspepsia, functional dyspepsia, gastroesophageal diseases, gastroesophageal reflux disease, erosive gastroesophageal reflux disease, maintenance therapy after treatment of erosive gastroesophageal reflux disease, non-erosive gastroesophageal reflux disease, gastritis, esophagitis, reflux esophagitis, peptic ulcer, gastric ulcer, duodenal ulcer, ulcer induced by nonsteroidal anti-inflammatory drugs (NSAIDs), ulcer induced by administration of drugs other than NSAIDs, alcoholic ulcer, stress-induced hyperacidity and ulcer, Helicobacter pylori (H. pylori) infection, Zollinger-Ellison syndrome, gastric cancer, and hyperacidity.

13. Use of a compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, for the prevention or treatment of diseases related to gastric acid secretion.

14. In the 13th paragraph, the disease related to gastric acid secretion is Use for the prevention or treatment of a disease related to gastric acid secretion, selected from the group consisting of gastrointestinal diseases, dyspepsia, functional dyspepsia, gastroesophageal diseases, gastroesophageal reflux disease, erosive gastroesophageal reflux disease, maintenance therapy after treatment of erosive gastroesophageal reflux disease, non-erosive gastroesophageal reflux disease, gastritis, esophagitis, reflux esophagitis, peptic ulcer, gastric ulcer, duodenal ulcer, ulcer induced by nonsteroidal anti-inflammatory drugs (NSAIDs), ulcer induced by administration of drugs other than NSAIDs, alcoholic ulcer, stress-induced hyperacidity and ulcer, Helicobacter pylori (H. pylori) infection, Zollinger-Ellison syndrome, gastric cancer, and hyperacidity.

15. Use of a compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, for the manufacture of a medicament for the prevention or treatment of diseases related to gastric acid secretion.

16. In paragraph 15, the disease related to gastric acid secretion is, A use for the manufacture of a medicament for preventing or treating a disease related to gastric acid secretion, selected from the group consisting of gastrointestinal diseases, dyspepsia, functional dyspepsia, gastroesophageal diseases, gastroesophageal reflux disease, erosive gastroesophageal reflux disease, maintenance therapy after treatment of erosive gastroesophageal reflux disease, non-erosive gastroesophageal reflux disease, gastritis, esophagitis, reflux esophagitis, peptic ulcer, gastric ulcer, duodenal ulcer, ulcer induced by nonsteroidal anti-inflammatory drugs (NSAIDs), ulcer induced by administration of drugs other than NSAIDs, alcoholic ulcer, stress-induced hyperacidity and ulcer, Helicobacter pylori (H. pylori) infection, Zollinger-Ellison syndrome, gastric cancer, and hyperacidity.

17. A method for preventing or treating a disease related to gastric acid secretion, comprising administering to a subject in need thereof a compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof.

18. In paragraph 17, the disease related to gastric acid secretion is, A method for preventing or treating a disease related to gastric acid secretion, selected from the group consisting of gastrointestinal diseases, dyspepsia, functional dyspepsia, gastroesophageal diseases, gastroesophageal reflux disease, erosive gastroesophageal reflux disease, maintenance therapy after treatment of erosive gastroesophageal reflux disease, non-erosive gastroesophageal reflux disease, gastritis, esophagitis, reflux esophagitis, peptic ulcer, gastric ulcer, duodenal ulcer, ulcer induced by nonsteroidal anti-inflammatory drugs (NSAIDs), ulcer induced by administration of drugs other than NSAIDs, alcoholic ulcer, stress-induced hyperacidity and ulcer, Helicobacter pylori (H. pylori) infection, Zollinger-Ellison syndrome, gastric cancer, and hyperacidity.