Heterobicyclic derivative and pharmaceutical composition comprising same

Abstract

A heterobicyclic derivative represented by chemical formula (I), according to the present invention, has a reversible proton pump inhibitory effect, and thus the heterobicyclic 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

Heterocyclic derivatives and pharmaceutical compositions containing the same

[0001] The present invention relates to a heterocyclic derivative and a pharmaceutical composition comprising the same. Specifically, the present invention relates to a heterocyclic 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]. Moreover, 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] Here, 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 heterobicyclic 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 heterobicyclic derivative, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0015] Another object of the present invention is to provide a pharmaceutical use of the heterocyclic derivative, and specifically, to provide a pharmaceutical composition for treating or preventing a gastric acid secretion-related disease, comprising the heterocyclic 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 heterobicyclic 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 , X 3 , L, R 1 , R 2 , R 3 , Y, A and n are 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" or "including" a component does not exclude other components, but rather implies the inclusion of other components, 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 "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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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 if 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. 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.

[0033] The term "multicyclic" refers to rings having more than one ring, including spiro rings, fused or condensed rings, or bridged rings.

[0034] 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, It 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 if it is a heterocyclic moiety having at least one ring in which electrons are delocalized by alternating single bonds and double bonds, i.e., a conjugated ð bond. 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.

[0035] 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.

[0036] 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.

[0037] The term "substitution" refers to replacing one or more hydrogen atoms in a molecular structure with a substituent, so as to result in a chemically stable compound from such substitution without exceeding the valence of 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 a carbon atom or heteroatom 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 thus, when illustrating a range of combinations of various groups and substituents including groups that are difficult to have substituents in the present specification, 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 further unsubstituted or substituted with a substituent selected from these groups of substituents.

[0038] 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).

[0039] 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.

[0040]

[0041] Heterocyclic bicyclic derivatives

[0042] One aspect of the present invention provides a compound represented by the following chemical formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0043] (I)

[0044] Here

[0045] X 1 , X 2 and X 3 are each independently C or N, at least one of which is N;

[0046] L is a single bond, sulfonyl, C 1-6 Alkylene, or C 1-6 It is alkylenesulfonyl;

[0047] R 1 , R 2 and R 3are each independently H, halogen, C 6-15 Aryl, C 3-15 Cycloalkyl, 5-15 membered heteroaryl, or 3-15 membered heterocycloalkyl, wherein aryl, cycloalkyl, 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;

[0048] A is C 1-3 Methylene substituted or unsubstituted with alkylamino or oxo;

[0049] Y is CH2 or NH;

[0050] n is an integer from 0 to 3.

[0051]

[0052] In one implementation example, X 1 , X 2 and X 3 One or two of them are N and the rest are C;

[0053] L is a single bond or sulfonyl;

[0054] R 1 and R 2 are each independently H, halogen, C 6-12 Aryl, C 3-12 Cycloalkyl, 5-12 membered heteroaryl, or 3-12 membered heterocycloalkyl, wherein aryl, cycloalkyl, 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-C1-6 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;

[0055] R 3 is H or halogen;

[0056] A is C 1-3 Methylene substituted or unsubstituted with alkylamino or oxo;

[0057] Y is CH2 or NH;

[0058] n is an integer from 1 to 3.

[0059]

[0060] In another implementation, X 1 , X 2 and X 3 One or two of them are N and the rest are C;

[0061] R 1 Silver H, halogen, C 6-12 Aryl, 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 with or without one or more substituents selected from the group consisting of alkoxy and acetyl, wherein said heteroaryl and heterocycloalkyl each independently contain 1 or 2 heteroatoms selected from the group consisting of N, S and O;

[0062] R 2 is C 6-12 Aryl or 5-12 membered heteroaryl, wherein aryl and heteroaryl are each independently halogen, C 1-6 Alkoxy and C 1-6Having or not having one or more substituents selected from alkyl, said heteroaryl each independently contains one or two heteroatoms selected from the group consisting of N, S and O.

[0063] In another embodiment, the residue of the above formula (I) Is or and;

[0064] A is C 1-6 Methylene substituted or unsubstituted with alkylamino or oxo;

[0065] Y is CH2 or NH;

[0066] n is an integer from 0 to 3.

[0067]

[0068] In another embodiment, the residue of the above formula (I) Is , , , , or and;

[0069] X 1 , X 2 and X 3 One or two of them are N and the rest are C;

[0070] Z is C 1-3 It's alkyl.

[0071]

[0072] In another embodiment, the residue of the above formula (I) Is , , , , , or , and Z is C 1-3 It's alkyl.

[0073]

[0074] In another implementation, R 1 silver , , , , , or and;

[0075] M is independently CH or N, and at least one M is N;

[0076] Q is independently NH, S, or O;

[0077] R A , R B , and R C are each independently H, 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.

[0078] In another implementation, R 2 Is or and;

[0079] M is independently CH or N, and at least one M is N;

[0080] R A , R B , and R C are each independently H, halogen, C 1-6 Alkyl, and C 1-6 Selected from the group consisting of alkoxy.

[0081]

[0082] In another implementation, X 1 , X 2 and X 3 Of these, one is N and the other two are C;

[0083] L is a single bond or sulfonyl;

[0084] R 1is phenyl, pyridyl, indolyl, dihydrobenzodioxinyl, furanyl, or imidazolyl, wherein phenyl, pyridyl, indolyl, dihydrobenzodioxinyl, furanyl, and imidazolyl each independently have or do not have one or two substituents selected from the group consisting of hydroxy, halogen, cyano, methyl, halomethyl, methoxy, methoxypropoxy, and acetyl;

[0085] R 2 is phenyl or pyridyl, wherein phenyl and pyridyl each independently have or do not have one to two substituents selected from the group consisting of halogen, methoxy and methyl;

[0086] R 3 is H or halogen;

[0087] A is methylene, optionally substituted with methylamino, ethylamino or oxo;

[0088] Y is CH2 or NH;

[0089] n is 1 or 2.

[0090]

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

[0092] In another implementation, R 2 Is , , , , , , or am.

[0093]

[0094] In specific examples, the scope of the present invention includes compounds selected from the group consisting of: or pharmaceutically acceptable salts or stereoisomers thereof.

[0095] 1> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-4,5,6,7-tetrahydro-1H-indol-4-amine;

[0096] 2> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-4,5,6,7-tetrahydro-1H-indol-4-amine hydrochloride;

[0097] 3> 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0098] 4> 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride;

[0099] 5> 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine fumarate;

[0100] 6> 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine 2,3-dihydroxysuccinate;

[0101] 7> 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine adipate;

[0102] 8> 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0103] 9> 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride;

[0104] 10> 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine 2-hydroxysuccinate;

[0105] 11> 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine adipate;

[0106] 12> 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine fumarate;

[0107] 13> 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine maleate;

[0108] 14> 1-((3-chlorophenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride;

[0109] 15> 1-((3-methoxyphenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride;

[0110] 16> 3-((2-(2-fluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)phenol hydrochloride;

[0111] 17> 2-(2-fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride;

[0112] 18> N-Ethyl-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0113] 19> 2-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride;

[0114] 20> 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0115] 21> 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine fumarate;

[0116] 22> 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride;

[0117] 23> 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (2E,4E)-hexa-2,4-dienoate;

[0118] 24> 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine adipate;

[0119] 25> 1-((3-chlorophenyl)sulfonyl)-2-(2,4-difluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride;

[0120] 26> 2-(2,4-difluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride;

[0121] 27> 3-((2-(2,4-difluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)phenol hydrochloride;

[0122] 28> 3-((2-(2,4-difluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)benzonitrile;

[0123] 29> 2-(2,4-difluorophenyl)-N-methyl-1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0124] 30> 2-(2,4-difluorophenyl)-N-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0125] 31> 2-(2,4-difluorophenyl)-1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0126] 32> 2-(2,4-difluorophenyl)-1-(furan-2-ylsulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0127] 33> 2-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0128] 34> 2-(2,4-difluorophenyl)-N-methyl-1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0129] 35> 2-(2,4-difluorophenyl)-1-((3,4-dimethylphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0130] 36> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0131] 37> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride;

[0132] 38> N-Methyl-2-phenyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0133] 39> N-Methyl-2-phenyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride;

[0134] 40> N-Methyl-1-((1-methyl-1H-indol-4-yl)sulfonyl)-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride;

[0135] 41> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-(pyridin-3-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride;

[0136] 42> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-(o-tolyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0137] 43> 2-(3-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0138] 44> 2-(2,4-difluorophenyl)-N-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0139] 45> (R)-2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0140] 46> (S)-2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine;

[0141] 47> (R)-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride;

[0142] 48> (S)-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride;

[0143] 49> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-4-amine hydrochloride;

[0144] 50> 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;

[0145] 51> 3-Chloro-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;

[0146] 52> 2-(2,4-difluorophenyl)-1-((3,4-difluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one;

[0147] 53> 2-(2,4-difluorophenyl)-1-((2,4-difluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one;

[0148] 54> 1-((3-acetylphenyl)sulfonyl)-2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one; and

[0149] 55> 2-(2-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one; and

[0150] 56> 1-((3-Fluorophenyl)sulfonyl)-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one.

[0151]

[0152] 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).

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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).

[0157] In specific examples, the pharmaceutically acceptable salt may be a hydrochloride salt, a dihydrochloride salt, an adipate salt, a maleate salt, a fumarate salt, a 2-hydroxysuccinate salt, a 2,3-dihydroxysuccinate salt, or a (2E,4E)-hexa-2,4-dienoate salt. In this way, the compound of the present invention may be provided in the form of each of the above salts.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162]

[0163] Uses of heterobicyclic derivatives

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] The present invention also provides a method for preventing or treating a disease related to gastric acid secretion, comprising administering to a subject in need thereof a compound represented by the above chemical formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] The 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).

[0183] 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.

[0184] 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.

[0185] The compound or composition of the present invention may be administered to a patient in a therapeutically effective amount or a pharmaceutically effective amount.

[0186] 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.

[0187] 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.

[0188] [Example]

[0189] 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.

[0190] The meanings of the abbreviations described in the examples below are as follows.

[0191] - AcOH: acetic acid

[0192] - ACN or MeCN: Acetonitrile

[0193] - AlCl3: aluminum chloride

[0194] - BBr3: Boron tribromide

[0195] - Boc: tert-butoxycarbonyl

[0196] - Brine: saturated sodium chloride solution

[0197] - mCPBA: 3-chloroperoxybenzoic acid

[0198] - Cs2CO3: Cesium carbonate

[0199] - CuI: Copper iodide

[0200] - DBU: 1,8-diazabicyclo[5,4,0]undec-7-en

[0201] - DIPEA: N,N-diisopropylethylamine

[0202] - DCM or MC: Dichloromethane

[0203] - DMAP: 4-dimethylaminopyridine

[0204] - DMF: N,N-dimethylformamide

[0205] - EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiamide

[0206] - EtOAc or EA: ethyl acetate

[0207] - EtOH: ethanol

[0208] - Et2O: ether

[0209] - EtNH2: Ethylamine

[0210] - Hex: n-hexane

[0211] - i-PrOH: Isopropyl alcohol

[0212] - K2CO3: Potassium carbonate

[0213] - Me: Methyl

[0214] - MeOH: methanol

[0215] - NaOMe: sodium methoxide

[0216] - NaOH: sodium hydroxide

[0217] - NaBH4: sodium borohydride

[0218] - Na2SO4: sodium sulfate

[0219] - NBS: N-bromosuccinimide

[0220] - NH4Cl: Ammonium chloride

[0221] - Pd(OAc)2: Palladium acetate

[0222] - Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0)

[0223] - PhI(OAc)2: (diacetoxyiodo)benzene

[0224] - PE: petroleum ether

[0225] - POCl3: phosphorus oxychloride

[0226] - RT or rt: room temperature

[0227] - TEA: Triethylamine

[0228] - TEMPO: 2,2,6,6-tetramethylpiperidine 1-oxyl

[0229] - TFA: Trifluoroacetic acid

[0230] - THF: Tetrahydrofuran

[0231] - TPAP: Tetrapropylammonium perruthenate

[0232] - TTIP: Titanium isopropanol

[0233] - XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0234]

[0235] NMR spectra were recorded on a JNM-ECZ500R / S1 (500 MHz 1 H, Jeol) or Avance (400 MHz 1 H, Bruker) 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) as appropriate. Microwave experiments were performed using Monowave 400 (Anton Paar).

[0236]

[0237] [Example 1] 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-4,5,6,7-tetrahydro-1H-indol-4-amine (7)

[0238]

[0239]

[0240] Step 1: 3-((2-hydroxy-1-phenylethyl)amino)cyclohex-2-en-1-one (3)

[0241] Cyclohexane-1,3-dione (1.5 g, 1 eq, 13.4 mmol) was dissolved in THF (33.4 mL, 0.4 M), and DL-phenylglycinol (2.2 g, 1.2 eq, 16.1 mmol) and molecular sieve 4Å (8.5 g) were added, respectively, and stirred at room temperature for 24 h. After completion of the reaction, Celite ® The residue was filtered and purified by silica gel column chromatography (5-10% MeOH / MC) to obtain 3-((2-hydroxy-1-phenylethyl)amino)cyclohex-2-en-1-one (yellow solid 1.2 g, yield 39%).

[0242] 1H NMR (500 MHz, DMSO-d6) δ 7.21 - 7.39 (m, 6 H), 5.01 (br s, 1 H), 4.60 (s, 1 H), 4.33 (br d,J=5.73 Hz, 1 H), 3.56 (br s, 2 H), 3.12 - 3.21 (m, 1 H), 2.41 (br t,J=5.44 Hz, 2 H), 1.94 - 2.22 (m, 2 H), 1.65 - 1.90 (m, 2 H); MH + 232

[0243]

[0244] Step 2: 2-Phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (4)

[0245] 3-((2-Hydroxy-1-phenylethyl)amino)cyclohex-2-en-1-one (1,066 mg, 1 eq, 4.61 mmol), tetrakis(triphenylphosphine)palladium(0) (532.6 mg, 0.1 eq, 0.461 mmol), potassium carbonate (274.0 mg, 2 eq, 9.22 mmol), and mesityl bromide (1.1 mL, 1.5 eq, 6.91 mmol) were dissolved in DMF and stirred at 150°C for 7 h. After completion of the reaction, H2O was added to quench the reaction and extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50-100% EA / PE) to obtain 2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (614 mg of orange solid, yield 63%).

[0246] 1H NMR (500 MHz, DMSO-d6) δ 11.68 - 11.92 (m, 1 H), 7.50 - 7.74 (m, 2 H), 7.37 (br t,J=7.73 Hz, 2 H), 7.17 - 7.26 (m, 1 H), 6.71 (br s, 1 H), 2.82 (br d,J=5.73 Hz, 2 H), 2.34 (br d,J=5.16 Hz, 2 H), 1.96 - 2.14 (m, 2 H); MH + 212.

[0247]

[0248] Step 3: 1-((3-fluorophenyl)sulfonyl)-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (6)

[0249] 2-Phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (300 mg, 1 eq, 1.42 mmol) was dissolved in DMF (3.6 mL, 0.4 M), and a 60% sodium hydride dispersion in mineral oil (227 mg, 4 eq, 5.68 mmol) was added and stirred at room temperature for 30 minutes. 3-Fluorobenzenesulfonyl chloride (757 μL, 4 eq, 5.68 mmol) was added and stirred at room temperature for 1 hour. After completion of the reaction, H2O was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by amino silica gel column chromatography (EA / Hex 20-50%) to obtain 1-((3-fluorophenyl)sulfonyl)-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (80 mg of pink solid, yield 15%).

[0250] 1H NMR (500 MHz, DMSO-d6) δ 7.57 - 7.72 (m, 2 H), 7.38 - 7.45 (m, 1 H), 7.29 - 7.37 (m, 3 H), 7.20 (br d,J=7.45 Hz, 1 H), 7.10 - 7.17 (m, 2 H), 6.41 - 6.46 (m, 1 H), 3.24 (br d,J=4.58 Hz, 2 H), 2.41 - 2.47 (m, 2 H), 2.13 (br d,J=5.73 Hz, 2 H); MH + 370

[0251]

[0252] Step 4: 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-4,5,6,7-tetrahydro-1H-indol-4-amine (7)

[0253] 1-((3-Fluorophenyl)sulfonyl)-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (70 mg, 1 eq, 0.19 mmol) was dissolved in methanol (4.7 mL, 0.04 M). Titanium(IV) isopropoxide (286.5 μL, 5 eq, 0.95 mmol) and 2 M methylamine in THF (3.78 mL, 10 eq, 1.89 mmol) were added, and the mixture was stirred at room temperature for 3 h. Sodium borohydride (71.5 mg, 10 eq, 1.89 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 h. After completion of the reaction, 3 mL of aqueous NaHCO3 solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (5-15% MeOH / MC) to obtain 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-4,5,6,7-tetrahydro-1H-indol-4-amine (yellow gel 34 mg, yield 47%).

[0254] 1H NMR (500 MHz, DMSO-d6) δ 7.55 - 7.65 (m, 2 H), 7.34 - 7.40 (m, 3 H), 7.22 - 7.29 (m, 3 H), 7.08 (dt,J=8.31, 1.86 Hz, 1 H), 6.31 (s, 1 H), 3.38 - 3.44 (m, 1 H), 2.79 (t,J=6.01 Hz, 2 H), 2.18 (s, 3 H), 1.87 - 1.96 (m, 1 H), 1.68 - 1.76 (m, 1 H), 1.57 - 1.67 (m, 1 H), 1.43 - 1.53 (m, 1 H); MS m / z 354 (MH + - NH2Me)

[0255]

[0256] [Example 2] 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-4,5,6,7-tetrahydro-1H-indol-4-amine hydrochloride (8)

[0257]

[0258] 1-((3-Fluorophenyl)sulfonyl)-N-methyl-2-phenyl-4,5,6,7-tetrahydro-1H-indol-4-amine (3 mg, 1 eq 0.01 mmol) was dissolved in ethyl acetate (1 mL, 0.01 M), and 1 M HCl in EtOAc (10 μL, 1.2 eq, 0.01 mmol) was added at 0°C. After 1 h of reaction, the reaction solution was concentrated to obtain 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-4,5,6,7-tetrahydro-1H-indol-4-amine hydrochloride (white solid 3.3 mg, yield 100%).

[0259] 1H NMR (500 MHz, DMSO-d6) δ 8.68 (br s, 1 H), 7.59 - 7.65 (m, 2 H), 7.35 - 7.44 (m, 3 H), 7.28 - 7.32 (m, 1 H), 7.17 - 7.22 (m, 2 H), 7.12 - 7.16 (m, 1 H), 6.47 (s, 1 H), 4.19 (br s, 1 H), 2.87 - 3.02 (m, 2 H), 2.54 (s, 3 H), 1.93 - 2.02 (m, 2 H), 1.72 - 1.89 (m, 2 H); MS m / z 354 (MH + - NH2Me - HCl)

[0260]

[0261] [Example 3] 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (20)

[0262]

[0263] Step 1: tert-Butyl 2-bromo-1H-pyrrole-1-carboxylate (10)

[0264] A solution of pyrrole (20 g, 20.62 mL) in THF (500 mL) was cooled to -78°C, N-bromosuccinimide (53 g, 1.0 eq) was added, and the mixture was stirred at -20°C for 2 hours. The solution was filtered under reduced pressure and cooled to -78°C. DMAP (728 mg, 0.02 eq), triethylamine (82.6 mL, 2.0 eq), and di-tert-butyl dicarbonate (103 mL, 1.5 eq) were added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with toluene, and then washed several times with distilled water and brine. The extracted organic layer was dried over Na2SO4, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 2-bromo-1H-pyrrole-1-carboxylate. The synthesized compound was used in the next reaction without purification (black oil, crude).

[0265]

[0266] Step 2: 2-(2-fluorophenyl)-1H-pyrrole (12)

[0267] 2-Fluorophenylboronic acid (50.1 g, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane complex (10 g, 0.05 eq), and K2CO3 (82.4 g, 2.0 eq) were added to a solution of tert-butyl 2-bromo-1H-pyrrole-1-carboxylate (51 g, crude) in toluene (600 mL), H2O (100 mL), and MeOH (100 mL), and the mixture was stirred at 80°C for 16 h. The reaction solution was filtered through a celite ®It was filtered using. After adding ethyl acetate and diluting, it was washed several times with distilled water and brine. The extracted organic layer was dried using Na2SO4 and filtered under reduced pressure. After dissolving the reactant in THF (1 L), 50 mL of sodium methoxide (Ca. 30% w / w in MeOH) was added and stirred at room temperature for 16 hours. The reaction solution 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 to obtain 2-(2-fluorophenyl)-1H-pyrrole. The synthesized compound was used in the next reaction without purification (black oil, crude).

[0268] 1 H NMR (500 MHz, DMSO-d6) δ 11.19 - 11.36 (m, 1 H), 7.65 - 7.81 (m, 1 H), 7.15 - 7.29 (m, 3 H), 6.91 (d,J=1.53 Hz, 1 H), 6.51 - 6.57 (m, 1 H), 6.16 (br d,J=8.41 Hz, 1 H); MH + 162

[0269]

[0270] Step 3: 5-(2-fluorophenyl)-1H-pyrrole-2-carbaldehyde (13)

[0271] 2-(2-Fluorophenyl)-1H-pyrrole (49 g, crude) was dissolved in DMF (35 mL, 1.5 eq). The solution was cooled to 0°C, phosphorus(V) oxychloride (41.8 mL, 1.5 eq) was slowly added, and the mixture was stirred at 40°C for 40 minutes. A solution of NaOH (35.8 g, 3.0 eq) in H2O (100 mL) was slowly added dropwise to the reaction solution, and the mixture was stirred at 110°C for 40 minutes. The reaction solution was diluted with ethyl acetate, and then 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 silica gel column chromatography to obtain 5-(2-fluorophenyl)-1H-pyrrole-2-carbaldehyde (brown solid 25.35 g, yield 45%).

[0272] 1 H NMR (500 MHz, DMSO-d6) δ 12.24 - 12.50 (m, 1 H), 9.56 (s, 1 H), 7.91 - 7.98 (m, 1 H), 7.37 - 7.43 (m, 1 H), 7.25 - 7.35 (m, 2 H), 7.11 (d,J=3.82 Hz, 1 H), 6.69 - 6.73 (m, 1 H); MH + 190

[0273]

[0274] Step 4: Ethyl (E)-3-(5-(2-fluorophenyl)-1H-pyrrol-2-yl)acrylate (15)

[0275] A solution of triethyl phosphonoacetate (31.9 mL, 1.2 eq) and Cs2CO3 (65.5 g, 1.5 eq) in 1,4-dioxane (660 mL) and H2O (6.6 mL) was stirred at room temperature for 30 minutes. 5-(2-fluorophenyl)-1H-pyrrole-2-carbaldehyde (25.35 g) was added to the reaction solution and stirred at 80°C for 16 hours. The reaction solution 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, washed with petroleum ether, and then filtered to obtain ethyl (E)-3-(5-(2-fluorophenyl)-1H-pyrrol-2-yl)acrylate. Yellow solid (25.8 g, yield 75%).

[0276] 1 H NMR (500 MHz, DMSO-d6) δ 11.60 (br s, 1 H), 7.74 - 7.88 (m, 1 H), 7.48 (d,J=15.89 Hz, 1 H), 7.20 - 7.32 (m, 4 H), 6.71 (d,J=3.82 Hz, 1 H), 6.59 (t,J=3.59 Hz, 1 H), 6.42 (d,J=15.89 Hz, 1 H), 4.12 (q,J=7.18 Hz, 2 H), 1.21 (t,J=7.11 Hz, 4 H); MH + 260

[0277]

[0278] Step 5: Ethyl 3-(5-(2-fluorophenyl)-1H-pyrrol-2-yl)propanoate (16)

[0279] To a solution of ethyl (E)-3-(5-(2-fluorophenyl)-1H-pyrrol-2-yl)acrylate (25.8 g) in ethanol (500 mL), 10% palladium on carbon (318 mg, 0.03 eq) was added and stirred at room temperature for 4 hours under hydrogen conditions. The reaction solution was transferred to Celite ®After filtration under reduced pressure using , the filtrate was concentrated under reduced pressure to obtain ethyl 3-(5-(2-fluorophenyl)-1H-pyrrol-2-yl)propanoate (yellow solid 24.7 g, yield 98%).

[0280] 1 H NMR (500 MHz, DMSO-d6) δ 10.94 (br s, 1 H), 7.61 - 7.70 (m, 1 H), 7.09 - 7.21 (m, 3 H), 6.37 (q,J=3.46 Hz, 1 H), 5.85 (dd,J=3.21, 2.60 Hz, 1 H), 4.03 (q,J=7.18 Hz, 2 H), 2.79 - 2.87 (m, 2 H), 2.57 - 2.65 (m, 2 H), 1.14 (t,J=7.11 Hz, 3 H); MH + 262

[0281]

[0282] Step 6: 3-(5-(2-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid (17)

[0283] Ethyl 3-(5-(2-fluorophenyl)-1H-pyrrol-2-yl)propanoate (24.7 g) was dissolved in THF (252 mL) and H2O (63 mL). KOH (10.6 g, 2.0 eq) was added and stirred at 80°C for 4 hours. The reaction solution was diluted with ethyl acetate and the pH was adjusted to 2–3. The solution was 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 3-(5-(2-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid (brown solid, 21.8 g, yield 99%).

[0284] 1H NMR (500 MHz, DMSO-d6) δ 11.76 - 12.47 (m, 1 H), 10.92 (br s, 1 H), 7.64 (td,J=8.02, 1.99 Hz, 1 H), 7.06 - 7.20 (m, 3 H), 6.37 (q,J=3.36) Hz, 1 H), 5.85 (dd,J=3.21, 2.60 Hz, 1 H), 2.80 (t,J=7.64 Hz, 2 H), 2.50 - 2.59 (m, 2 H); MH + 234

[0285]

[0286] Step 7: 2-(2-fluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (18)

[0287] Polyphosphoric acid (9.36 g, 3.0 eq) was placed in a round-bottomed flask and heated to 100°C. 3-(5-(2-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid (21.8 g) was added to the solution and stirred at 100°C for 4 hours. The reaction solution was dissolved in methanol, alkalized with an aqueous NaHCO3 solution, and washed several times with ethyl acetate, distilled water, and brine. 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 then concentrated under reduced pressure. The concentrated reaction product was solidified using CH2Cl2 and hexane, and then filtered under reduced pressure to obtain 2-(2-fluorophenyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (brown solid, 17.5 g, yield 87%).

[0288] 1H NMR (500 MHz, DMSO-d6) δ 11.93 (br s, 1 H), 7.70 (td,J=7.83, 1.60 Hz, 1 H), 7.19 - 7.33 (m, 3 H), 6.51 (d,J=2.45 Hz, 1 H), 2.90 - 2.96 (m, 2 H), 2.71 - 2.77 (m, 2 H); MH + 216

[0289]

[0290] Step 8: 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (19)

[0291] 2-(2-Fluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (200 mg, 1 eq, 0.93 mmol) was dissolved in DMF (3.1 mL, 0.3 M) and stirred for 5 minutes under nitrogen at 0°C. A 60% sodium hydride dispersion in mineral oil (89.2 mg, 4 eq, 3.72 mmol) was added and stirred for 1 hour. 3-Fluorobenzenesulfonyl chloride (362.0 μL, 3 eq, 2.79 mmol) was added and stirred at room temperature for 2 hours. After completion of the reaction, NaHCO3(aq) was added at 0°C to terminate the reaction and the mixture was extracted twice with ethyl acetate. Sodium sulfate was added to the organic layer, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by normal silica gel column chromatography (50-100% EA / Hex) to obtain 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (brown gel 267 mg, yield 74%).

[0292] 1H NMR (500 MHz, DMSO-d6) δ 7.66 - 7.70 (m, 2 H), 7.55 (tdd,J=7.80, 5.58, 1.72 Hz, 1 H), 7.36 - 7.39 (m, 1 H), 7.26 (dt,J=8.02, 2.29 Hz, 1 H), 7.18 - 7.21 (m, 2 H), 7.10 (td,J=7.45, 1.72 Hz, 1 H), 6.51 (s, 1 H), 3.25 - 3.32 (m, 2 H), 2.84 - 2.89 (m, 2 H); MH + 374

[0293]

[0294] Step 9: 2-(2-Fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (20)

[0295] 2-(2-Fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (267 mg, 1 eq, 0.72 mmol) was dissolved in MeOH (17 mL, 0.04 M), titanium(IV) isopropoxide (1.1 mL, 5 eq, 3.58 mmol) and 2 M methylamine in THF (3.6 mL, 10 eq, 7.15 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Sodium borohydride (270.5 mg, 10 eq, 7.15 mmol) was slowly added, and the mixture was stirred for 1 hour. After completion of the reaction, saturated aqueous NaHCO3 solution was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by amino silica gel column chromatography (50-100% EA / Hex) to obtain 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow gel 127 mg, yield 46%).

[0296] 1H NMR (500 MHz, DMSO-d6) δ 7.59 - 7.66 (m, 2 H), 7.46 - 7.52 (m, 1 H), 7.30 (br d,J=6.87 Hz, 1 H), 7.18 - 7.24 (m, 2 H), 7.10 - 7.16 (m, 2 H), 6.33 (s, 1 H), 3.97 (br s, 1 H), 3.01 - 3.10 (m, 1 H), 2.85 - 2.95 (m, 1 H), 2.57 - 2.66 (m, 1 H), 2.27 (s, 3 H), 2.07 - 2.15 (m, 1 H); MS m / z 358 (MH + - NH2Me)

[0297]

[0298] [Example 4] 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (21)

[0299]

[0300] 2-(2-Fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (127 mg, 1 eq, 0.33 mmol) was dissolved in ethyl acetate (0.5 mL, 0.7 M) and stirred at 0°C for 2 min. 1 M HCl in EA (392 μL, 1.2 eq) was added, and the reaction temperature was slowly raised to room temperature. After stirring for 30 min, the mixture was filtered and filtered to obtain 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (54 mg of ivory solid, yield 39%).

[0301] 1H NMR (500 MHz, DMSO-d6) δ 7.61 - 7.68 (m, 2 H), 7.49 - 7.57 (m, 1 H), 7.30 - 7.35 (m, 1 H), 7.20 - 7.25 (m, 2 H), 7.14 - 7.19 (m, 1 H), 7.11 (td,J=7.57, 1.68 Hz, 1 H), 6.46 (s, 1 H), 4.41 (br d,J=6.11 Hz, 1 H), 3.16 - 3.20 (m, 1 H), 3.01 - 3.10 (m, 1 H), 2.75 - 2.86 (m, 1 H), 2.52 (s, 3 H), 2.37 - 2.41 (m, 1 H); MS m / z 358 (MH + - NH2Me - HCl)

[0302]

[0303] [Example 5] 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine fumarate (22)

[0304]

[0305] 2-(2-Fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (100 mg, 1 eq) was dissolved in ethyl acetate (1 mL, 10 v / w), fumaric acid (32.9 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 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine fumarate (white solid 88 mg, yield 67.8%).

[0306] 1H NMR (500 MHz, DMSO-d6) δ 7.61 - 7.65 (m, 2 H), 7.48 - 7.54 (m, 1 H), 7.28 - 7.34 (m, 1 H), 7.18 - 7.25 (m, 2 H), 7.13 - 7.17 (m, 1 H), 7.10 (td,J=7.57, 1.68 Hz, 1 H), 6.44 (s, 2 H), 6.41 (s, 1 H), 4.32 (br d,J=7.03 Hz, 1 H), 3.12 - 3.21 (m, 1 H), 3.01 (ddd,J=16.47, 9.13, 3.74 Hz, 1 H), 2.74 (dtd, J=14.04, 8.53, 5.58 Hz, 1 H), 2.44 (s, 3 H), 2.34 - 2.41 (m, 1 H); MS m / z 358 (MH + - NH2Me - C4H4O4)

[0307]

[0308] [Example 6] 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine 2,3-dihydroxysuccinate (23)

[0309]

[0310] 2-(2-Fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (100 mg, 1 eq) was dissolved in ethyl acetate (1 mL, 10 v / w), tartaric acid (42.5 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 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine 2,3-dihydroxysuccinate (white solid 90 mg, yield 65.4%).

[0311] 1H NMR (500 MHz, DMSO-d6) δ 7.61 - 7.66 (m, 2 H), 7.49 - 7.56 (m, 1 H), 7.29 - 7.37 (m, 1 H), 7.18 - 7.25 (m, 2 H), 7.15 (dt,J=8.48, 1.18 Hz, 1 H), 7.10 (td,J=7.53, 1.76 Hz, 1 H), 6.45 (d,J=1.68 Hz, 1 H), 4.41 (br d,J=7.34 Hz, 1 H), 3.88 (s, 2 H), 3.13 - 3.24 (m, 1 H), 3.04 (ddd,J=16.58, 9.09, 3.52 Hz, 1 H), 2.78 (dtd,J=14.14, 8.67, 5.65 Hz, 1 H), 2.34 - 2.43 (m, 1 H); MS m / z 358 (MH + - NH2Me - C4H6O6)

[0312]

[0313] [Example 7] 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine adipate (24)

[0314]

[0315] 2-(2-Fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (100 mg, 1 eq) was dissolved in ethyl acetate (1 mL, 10 v / w), adipic acid (42.5 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 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine adipate (110 mg of white solid, yield 79.3%).

[0316] 1H NMR (500 MHz, DMSO-d6) δ 7.57 - 7.67 (m, 2 H), 7.45 - 7.53 (m, 1 H), 7.30 (dt,J=7.11, 1.72 Hz, 1 H), 7.17 - 7.24 (m, 2 H), 7.08 - 7.16 (m, 2 H), 6.32 (s, 1 H), 3.93 - 3.97 (m, 1 H), 3.00 - 3.10 (m, 1 H), 2.90 (ddd,J=16.28, 8.94, 4.74 Hz, 1 H), 2.56 - 2.65 (m, 1 H), 2.25 (s, 3 H), 2.15 - 2.19 (m, 4 H), 2.07 - 2.14 (m, 1 H), 1.46 - 1.52 (m, 4 H); MS m / z 358 (MH + - NH2Me - C6H 10 O4)

[0317]

[0318] [Example 8] 2-(2-Fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (27)

[0319]

[0320]

[0321] Step 1: 2-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (26)

[0322] 2-(2-Fluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (2 g, 1 eq, 9.29 mmol) was dissolved in THF (31 mL, 0.3 M) and stirred for 5 minutes at 0°C under N2. A 60% sodium hydride dispersion in mineral oil (558 mg, 1.5 eq, 13.94 mmol) was added and stirred for 1 hour. Pyridine-3-sulfonyl chloride (1.4 mL, 1.1 eq, 10.22 mmol) was added and stirred at room temperature for 16 hours. After completion of the reaction, NaHCO3(aq) was added at 0°C to terminate the reaction and extracted twice with ethyl acetate. Sodium sulfate was added to the organic layer, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by amino silica gel column chromatography (0-5% MeOH / MC) to obtain 2-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (1.8 g of orange solid, yield 54%).

[0323] 1 H NMR (500 MHz, DMSO-d6) δ 8.93 (dd,J=4.74, 1.53 Hz, 1 H), 8.56 (dd,J=2.52, 0.69 Hz, 1 H), 7.95 (ddd,J=8.18, 2.52, 1.53 Hz, 1 H), 7.63 (ddd,J=8.18, 4.81, 0.76 Hz, 1 H), 7.51 - 7.60 (m, 1 H), 7.16 - 7.26 (m, 2 H), 7.10 (td,J=7.49, 1.83 Hz, 1 H), 6.52 (s, 1 H), 3.35 - 3.43 (m, 2 H), 2.87 (dt,J=4.85, 2.24 Hz, 2 H); MH + 357

[0324]

[0325] Step 2: 2-(2-Fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (27)

[0326] 2-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (1.8 g, 1 eq, 5.05 mmol) was dissolved in DCM (127 mL, 0.04 M), titanium(IV) isopropoxide (4.6 mL, 3 eq, 15.2 mmol) and 2 M methylamine in THF (50.5 mL, 5 eq, 25.3 mmol) were added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and methanol was added to perform azeotropic concentration twice. Methanol (50.5 mL, 0.1 M) was added to the concentrated residue, and the temperature was lowered to 0°C. Sodium borohydride (573 mg, 3 eq, 15.1 mmol) was slowly added and stirred for 1 hour. After completion of the reaction, saturated aqueous NaHCO3 solution was added to quench the reaction and extracted twice with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by amino silica gel column chromatography (10-20% MeOH / MC) to obtain 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow gel 0.9 g, yield 48%).

[0327] 1H NMR (500 MHz, DMSO-d6) δ 8.87 (dd,J=1.5, 4.9 Hz, 1H), 8.49 (dd,J=0.8, 2.4 Hz, 1H), 7.83 (d,J=8.1 Hz, 1H), 7.61 (ddd,J=0.8, 4.8, 8.2 Hz, 1H), 7.46 - 7.52 (m, 1H), 7.22 (t,J=8.2 Hz, 2H), 7.11 - 7.17 (m, 1H), 6.32 (s, 1H), 3.85 - 3.90 (m, 1H), 3.00 - 3.10 (m, 1H), 2.90 (ddd,J=5.0, 8.9, 16.2 Hz, 1H), 2.55 - 2.62 (m, 1H), 2.21 (s, 3H), 2.02 - 2.13 (m, 1H); MS m / z 341 (MH + - NH2Me)

[0328]

[0329] [Example 9] 2-(2-Fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride (28)

[0330]

[0331] 2-(2-Fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (107 mg, 1 eq, 0.288 mmol) was dissolved in ethyl acetate (1 mL, 0.3 M) and stirred at room temperature for 2 minutes. 1 M HCl in EA (0.72 mL, 2.5 eq) was added, and the reaction temperature was slowly raised to room temperature. After stirring for 30 minutes, the mixture was filtered, and the filtered solid was dissolved in methanol and concentrated to give 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride (111.1 mg, 87%, green solid).

[0332] 1H NMR (500 MHz, DMSO-d6) δ 8.90 (dd,J=1.4, 4.9 Hz, 1 H), 8.85 - 8.97 (m, 2 H), 8.53 (d,J=2.3 Hz, 1 H), 7.87 (td,J=2.1, 7.7 Hz, 1 H), 7.60 - 7.65 (m, 1 H), 7.53 (ddt,J=1.7, 5.4, 7.9 Hz, 1 H), 7.19 - 7.26 (m, 2 H), 7.08 (dt,J=1.7, 7.4 Hz, 1 H), 6.50 (s, 1 H), 4.47 (br dd,J=1.7, 5.7 Hz, 1 H), 3.18 - 3.28 (m, 1 H), 3.09 (ddd,J=3.4, 9.2, 16.6 Hz, 1 H), 2.82 (dtd,J=5.7, 8.6, 14.3 Hz, 1 H), 2.55 (t,J=5.4 Hz, 3 H), 2.43 (tdd,J=3.2, 8.2, 14.5 Hz, 1 H); MS m / z 341 (MH + - NH2Me-2HCl)

[0333]

[0334] [Example 10] 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine 2-hydroxysuccinate (29)

[0335]

[0336] 2-(2-Fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (5.86 g, 1 eq, 15.8 mmol) was added to ethyl acetate (31.5 mL, 0.5 M). DL-Malic acid (2.2 g, 1.05 eq, 16.6 mmol) was added and stirred vigorously for 24 h. The mixture was filtered to obtain 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine 2-hydroxysuccinate (ivory solid, 6.7 g, yield 84%).

[0337] 1 H NMR (500 MHz, DMSO-d6) δ 8.91 (dd,J=1.5, 4.7 Hz, 1 H), 8.53 (dd,J=0.6, 2.4 Hz, 1 H), 7.86 (ddd,J=1.7, 2.5, 8.2 Hz, 1 H), 7.63 (ddd,J=0.8, 4.8, 8.2 Hz, 1 H), 7.51 - 7.57 (m, 1 H), 7.20 - 7.25 (m, 2 H), 7.10 (dt,J=1.6, 7.4 Hz, 1 H), 6.47 (s, 1 H), 4.43 (br d,J=5.3 Hz, 1 H), 3.86 (br dd,J=3.4, 10.5 Hz, 1 H), 3.21 (br dd,J=7.7, 16.6 Hz, 2 H), 3.04 - 3.12 (m, 1 H), 2.76 - 2.86 (m, 1 H), 2.53 - 2.55 (m, 3 H), 2.45 - 2.49 (m, 1) H), 2.35 - 2.42 (m, 1H), 2.29 - 2.34 (m, 1H); MS m / z 341 (MH + - NH2Me - C4H6O5)

[0338]

[0339] [Example 11] 2-(2-Fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine adipate (30)

[0340]

[0341] 2-(2-Fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (100 mg, 1 eq) was dissolved in ethyl acetate (1 mL, 10 v / w), adipic acid (43.3 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 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine adipate (ivory solid, 71 mg, yield 64.6%).

[0342] 1 H NMR (500 MHz, DMSO-d6) δ 8.87 (dd,J=4.81, 1.45 Hz, 1 H), 8.50 (d,J=2.29 Hz, 1 H), 7.81 - 7.85 (m, 1 H), 7.61 (dd,J=8.10, 4.89 Hz, 1 H), 7.49 (tdd, J=7.74, 5.46, 1.83 Hz, 1 H), 7.19 - 7.24 (m, 2 H), 7.11 - 7.17 (m, 1 H), 6.33 (s, 1 H), 3.91 - 3.95 (m, 1 H), 3.03 - 3.11 (m, 1 H), 2.92 (ddd,J=16.35, 8.94, 4.81 Hz, 1 H), 2.60 (dtd,J=13.01, 8.43, 4.97 Hz, 1 H), 2.24 (s, 3 H), 2.14 - 2.18 (m, 2 H), 2.06 - 2.14 (m, 1) H), 1.46 - 1.51 (m, 2 H), 1.17 (t,J=7.11 Hz, 1 H); MS m / z 341 (MH + - NH2Me - C6H 10 O4)

[0343]

[0344] [Example 12] 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine fumarate (31)

[0345]

[0346] 2-(2-Fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (100 mg, 1 eq) was dissolved in ethyl acetate (1 mL, 10 v / w), fumaric acid (34.3 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 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine fumarate (ivory solid, 88 mg, yield 67.8%).

[0347] 1 H NMR (500 MHz, DMSO-d6) δ 8.89 (dd,J=4.89, 1.53 Hz, 1 H), 8.51 (d,J=2.45 Hz, 1 H), 7.84 - 7.88 (m, 1 H), 7.61 (ddd,J=8.21, 4.85, 0.69 Hz, 1 H), 7.48 - 7.55 (m, 1 H), 7.18 - 7.24 (m, 2 H), 7.09 (td,J=7.49, 1.68 Hz, 1 H), 6.45 (s, 2 H), 6.43 (s, 1 H), 4.35 (br d,J=7.34 Hz, 1 H), 3.15 - 3.24 (m, 1 H), 3.04 (ddd,J=16.47, 9.06, 3.67 Hz, 1 H), 2.76 (dtd,J=14.04, 8.57, 5.65 Hz, 1 H), 2.45 (s, 3 H), 2.37 - 2.43 (m, 1 H), 2.08 (s, 1 H), 1.99 (s, 1 H), 1.17 (t,J=7.11 Hz, 1 H); MS m / z 341 (MH + - NH2Me - C4H4O4)

[0348]

[0349] [Example 13] 2-(2-Fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine maleate (32)

[0350]

[0351] 2-(2-Fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (50 mg, 1 eq) was dissolved in ethyl acetate (1 mL, 10 v / w), maleic acid (17.2 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 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine maleate (white solid 50 mg, yield 76.1%).

[0352] 1H NMR (500 MHz, DMSO-d6) δ 8.91 (dd,J=4.81, 1.45 Hz, 1 H), 8.68 (br s, 2 H, 8.54 (dd,J=2.45, 0.61 Hz, 1 H), 7.84 - 7.88 (m, 1 H), 7.63 (ddd,J=8.25, 4.89, 0.76 Hz, 1 H), 7.51 - 7.57 (m, 1 H), 7.20 - 7.25 (m, 2 H), 7.10 (td,J=7.45, 1.60 Hz, 1 H), 6.48 (s, 1 H), 6.01 (s, 2H), 4.49 (br d,J=7.64 Hz, 1 H), 4.03 (q,J=7.03 Hz, 1 H), 3.33 (s, 10 H), 3.18 - 3.26 (m, 1 H), 3.05 - 3.15 (m, 1 H), 2.83 (dtd,J=14.27, 8.68, 5.81 Hz, 1 H), 2.57 (s, 3 H), 2.41 (ddt,J=14.48, 8.18, 3.27 Hz, 1 H), 1.99 (s, 1 H), 1.91 (s, 1 H), 1.17 (t,J=7.11 Hz, 1 H); MS m / z 341 (MH + - NH2Me - C4H4O4)

[0353]

[0354] [Example 14] 1-((3-chlorophenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (36)

[0355]

[0356]

[0357] Step 1: 1-((3-chlorophenyl)sulfonyl)-2-(2-fluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (34)

[0358] 2-(2-Fluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (200 mg, 1 eq, 1.01 mmol) was dissolved in DMF (3.4 mL, 0.3 M) and stirred for 5 minutes under nitrogen at 0°C. A 60% sodium hydride dispersion in mineral oil (162 mg, 4 eq, 4.06 mmol) was added and stirred for 1 hour. 3-Chlorobenzenesulfonyl chloride (284 μL, 2 eq, 2.02 mmol) was added and stirred at room temperature for 30 minutes. After completion of the reaction, NaHCO3(aq) was added at 0°C to terminate the reaction and extracted twice with ethyl acetate. Sodium sulfate was added to the organic layer, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by amino silica gel column chromatography (35-50% EA / Hex) to give 1-((3-chlorophenyl)sulfonyl)-2-(2-fluorophenyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (brown gel 251 mg, yield 63%).

[0359] 1 H NMR (500 MHz, DMSO-d6) δ 7.87 (ddd,J=7.91, 2.10, 1.15 Hz, 1 H), 7.53 - 7.63 (m, 3 H), 7.30 (t,J=1.76 Hz, 1 H), 7.18 - 7.24 (m, 2 H), 7.09 (td,J=7.49, 1.83 Hz, 1 H), 6.51 (s, 1 H), 3.27 - 3.30 (m, 2 H), 2.86 (dt,J=4.85, 2.24 Hz, 2 H); MH + 390

[0360]

[0361] Step 2: 1-((3-chlorophenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (35)

[0362] 1-((3-Chlorophenyl)sulfonyl)-2-(2-fluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (100 mg, 1 eq, 0.26 mmol) was dissolved in MeOH (6.4 mL, 0.04 M), titanium(IV) isopropoxide (388 μL, 5 eq, 1.3 mmol) and 2 M methylamine in THF (1.2 mL, 10 eq, 2.6 mmol) were added, and the mixture was stirred at room temperature for 10 h. Sodium borohydride (97 mg, 10 eq, 2.6 mmol) was slowly added, and the mixture was stirred for 5 min. After completion of the reaction, saturated aqueous NaHCO3 solution was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by amino silica gel column chromatography (5-15% MeOH / MC) to obtain 1-((3-chlorophenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow gel 24 mg, yield 23%).

[0363] 1 H NMR (500 MHz, DMSO-d6) δ 7.83 (ddd,J=8.06, 2.03, 0.92 Hz, 1 H), 7.61 (t,J=8.10 Hz, 1 H), 7.51 - 7.56 (m, 2 H), 7.47 - 7.53 (m, 1 H), 7.34 - 7.41 (m, 1 H), 7.20 - 7.26 (m, 2 H), 7.09 - 7.15 (m, 1 H), 6.39 (s, 1 H), 4.15 - 4.29 (m, 1 H), 3.08 - 3.17 (m, 1 H), 2.94 - 3.02 (m, 1 H), 2.62 - 2.67 (m, 1 H), 2.40 (s, 1 H), 2.19 - 2.28 (m, 1 H); MS m / z 374 (MH + - NH2Me)

[0364]

[0365] Step 3: 1-((3-chlorophenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (36)

[0366] 1-((3-Chlorophenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (24 mg, 1 eq, 0.06 mmol) was dissolved in ethyl acetate (0.5 mL, 0.1 M) and stirred at 0°C for 2 min. 1 M HCl in EA (71 μL, 1.2 eq) was added, and the reaction temperature was slowly raised to room temperature. After stirring for 30 min, the mixture was filtered. The filtered solid was dissolved in methanol and concentrated to give 1-((3-chlorophenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (ivory solid, 9.1 mg, yield 35%).

[0367] 1 H NMR (500 MHz, DMSO-d6) δ 8.61 (br d,J=9.78 Hz, 1 H), 7.85 (ddd,J=8.06, 2.10, 0.84 Hz, 1 H), 7.61 (t,J=8.02 Hz, 1 H), 7.52 - 7.58 (m, 1 H), 7.48 - 7.51 (m, 1 H), 7.20 - 7.25 (m, 3 H), 7.10 (td,J=7.45, 1.45 Hz, 1 H), 6.46 (s, 1 H), 4.44 (br d,J=6.42 Hz, 1 H), 3.16 - 3.25 (m, 1 H), 3.02 - 3.10 (m, 1 H), 2.76 - 2.86 (m, 1 H), 2.53 (s, 3 H), 2.37 - 2.43 (m, 1 H); MS m / z 374 (MH + - NH2Me - HCl)

[0368]

[0369] [Example 15] 1-((3-methoxyphenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (40)

[0370]

[0371]

[0372] Step 1: 2-(2-fluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (38)

[0373] 2-(2-Fluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (1 g, 1 eq, 4.65 mmol) was dissolved in DMF (15 mL, 0.3 M) and stirred for 5 minutes under nitrogen at 0°C. A 60% sodium hydride dispersion in mineral oil (743.4 mg, 4 eq, 18.58 mmol) was added and stirred for 1 hour. 3-Methoxybenzenesulfonyl chloride (789.1 μL, 1.2 eq, 5.58 mmol) was added and stirred at room temperature for 30 minutes. After completion of the reaction, NaHCO3(aq) was added at 0°C to terminate the reaction and extracted twice with ethyl acetate. Sodium sulfate was added to the organic layer, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by amino silica gel column chromatography (35-50% EA / Hex) to obtain 2-(2-fluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (brown gel 510 mg, yield 31%).

[0374] 1H NMR (500 MHz, DMSO-d6) δ 7.53 - 7.58 (m, 1 H), 7.50 (d,J=8.10 Hz, 1 H), 7.34 (ddd,J=8.41, 2.60, 0.76 Hz, 1 H), 7.16 - 7.25 (m, 3 H), 7.12 (td,J=7.53, 1.76 Hz, 1 H), 6.80 - 6.83 (m, 1 H), 6.48 (s, 1 H), 3.74 (s, 3 H), 3.29 - 3.32 (m, 2 H), 2.86 (dt,J=4.78, 2.27 Hz, 2H); MH + 386

[0375]

[0376] Step 2: 1-((3-methoxyphenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (39)

[0377] 2-(2-Fluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (190 mg, 1 eq, 0.49 mmol) was dissolved in MeOH (12.3 mL, 0.04 M). Titanium(IV) isopropoxide (745.3 μL, 5 eq, 2.5 mmol) and 2 M methylamine in THF (2.5 mL, 10 eq, 4.9 mmol) were added, and the mixture was stirred at room temperature for 10 h. Sodium borohydride (186.5 mg, 10 eq, 4.9 mmol) was slowly added, and the mixture was stirred for 5 min. After completion of the reaction, saturated aqueous NaHCO3 solution was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography (5-15% MeOH / MC) to obtain 1-((3-methoxyphenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow gel 71 mg, yield 36%).

[0378] 1 H NMR (500 MHz, DMSO-d6) δ 7.44 - 7.51 (m, 2 H), 7.26 (ddd,J=8.33, 2.60, 0.84 Hz, 1 H), 7.18 - 7.23 (m, 2 H), 7.13 - 7.18 (m, 1 H), 7.06 - 7.10 (m, 1 H), 6.75 - 6.78 (m, 1 H), 6.27 (s, 1 H), 3.83 - 3.89 (m, 1 H), 3.73 (s, 3 H), 2.97 - 3.07 (m, 1 H), 2.82 - 2.90 (m, 1 H), 2.53 - 2.61 (m, 1 H), 2.21 (s, 3 H), 1.98 - 2.09 (m, 1 H); MS m / z 370 (MH + - NH2Me)

[0379]

[0380] Step 3: 1-((3-methoxyphenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (40)

[0381] 1-((3-Methoxyphenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (77 mg, 1 eq, 0.19 mmol) was dissolved in ethyl acetate (0.5 mL, 0.4 M) and stirred at 0°C for 2 minutes. 1 M HCl in EA (230.7 μL, 1.2 eq) was added, and the reaction temperature was slowly raised to room temperature. After stirring for 30 minutes, the mixture was filtered. The filtered solid was dissolved in methanol and concentrated to give 1-((3-methoxyphenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (ivory solid, 69.7 mg, yield 82%).

[0382] 1H NMR (500 MHz, DMSO-d6) δ 8.75 (br s, 1 H), 7.48 - 7.55 (m, 2 H), 7.31 (ddd,J=8.37, 2.56, 0.84 Hz, 1 H), 7.20 - 7.26 (m, 2 H), 7.10 - 7.14 (m, 2 H), 6.78 - 6.79 (m, 1 H), 6.45 (s, 1 H), 4.45 (br d,J=7.34 Hz, 1 H), 3.74 (s, 3 H), 3.14 - 3.23 (m, 1 H), 2.99 - 3.06 (m, 1 H), 2.80 (dtd,J=14.21, 8.60, 8.60, 5.58 Hz, 1 H), 2.53 (s, 3 H), 2.36 - 2.43 (m, 1 H); MS m / z 370 (MH + - NH2Me - HCl)

[0383]

[0384] [Example 16] 3-((2-(2-fluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)phenol hydrochloride (42)

[0385]

[0386]

[0387] Step 1: 3-((2-(2-fluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)phenol (41)

[0388] 1-((3-Methoxyphenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (156 mg, 1 eq, 0.39 mmol) was dissolved in DCM (1.3 mL, 0.3 M) and stirred at 0°C for 5 min. 1 M BBr3 (1.2 mL, 3 eq, 1.17 mmol) 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. A small amount of DCM was added to the concentrated residue, and the insoluble white solid was filtered to obtain 3-((2-(2-fluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)phenol as a filter cake (95 mg of ivory solid, yield 63%).

[0389] 1 H NMR (500 MHz, DMSO-d6) δ 8.53 (d,J=2.60 Hz, 1 H), 7.43 - 7.50 (m, 1 H), 7.29 - 7.34 (m, 1 H), 7.17 - 7.23 (m, 3 H), 7.15 (dd,J=7.34, 1.99 Hz, 1 H), 6.76 - 6.84 (m, 2 H), 6.24 - 6.26 (m, 1 H), 3.84 - 3.91 (m, 1 H), 2.96 - 3.05 (m, 1 H), 2.86 - 2.94 (m, 1 H), 2.77 - 2.85 (m, 1 H), 2.22 (s, 3 H), 1.74 - 1.81 (m, 1 H); MS m / z 356 (MH + - NH2Me)

[0390]

[0391] Step 2: 3-((2-(2-fluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)phenol hydrochloride (42)

[0392] 3-((2-(2-fluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)sulfonyl)phenol (95 mg, 1 eq, 0.25 mmol) was dissolved in methanol (2 mL, 1 M) and stirred at 0°C for 2 minutes. 0.5 M HCl in MeOH (590 μL, 1.2 eq, 0.3 mmol) was added, and the reaction temperature was slowly raised to room temperature and stirred for 16 hours. The reaction solution was concentrated to obtain 3-((2-(2-fluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)sulfonyl)phenol hydrochloride (ivory solid 100.7 mg, yield 97%).

[0393] 1 H NMR (500 MHz, DMSO-d6) δ 10.39 (br s, 1 H), 8.98 (br s, 1 H), 7.48 - 7.54 (m, 1 H), 7.33 - 7.37 (m, 1 H), 7.18 - 7.24 (m, 2 H), 7.07 - 7.11 (m, 2 H), 6.85 - 6.88 (m, 2 H), 6.45 (s, 1 H), 4.43 - 4.47 (m, 1 H), 3.13 - 3.23 (m, 1 H), 2.94 - 3.06 (m, 1 H), 2.80 (dtd,J=14.18, 8.73, 5.65 Hz, 1 H), 2.52 (s, 3 H), 2.38 - 2.46 (m, 1 H); MS m / z 356 (MH + - NH2Me - HCl)

[0394]

[0395] [Example 17] 2-(2-fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (47)

[0396]

[0397]

[0398] Step 1: 2-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (43)

[0399] 2-(2-Fluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (867 mg, 2.25 mmol, 1 eq) was dissolved in DCM (7.5 mL, 0.3 M) and stirred at 0°C for 5 minutes. 1 M BBr3 (3.4 mL, 1.5 eq) was added and stirred at room temperature for 3 hours. 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. A small amount of DCM was added to the concentrated residue, and the insoluble white solid was filtered to obtain 2-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (652 mg of white solid, yield 78%).

[0400] 1 H NMR (500 MHz, DMSO-d6) δ 9.90 - 10.72 (br s, 1 H), 7.50 - 7.57 (m, 1 H), 7.36 (t,J=8.02 Hz, 1 H), 7.17 - 7.25 (m, 2 H), 7.07 - 7.14 (m, 2 H), 6.92 (ddd,J=7.83, 1.80, 0.76 Hz, 1 H), 6.81 (t,J=2.14 Hz, 1 H), 6.47 (s, 1 H), 3.27 (dt,J=4.81, 2.18 Hz, 2 H), 2.86 (dt,J=4.85, 2.24 Hz, 2 H); MH + 372

[0401]

[0402] Step 2: 2-(2-fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (45)

[0403] 2-(2-Fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (652 mg, 1 eq, 1.76 mmol) was dissolved in DMF (5.9 mL, 0.3 M), and potassium carbonate (485.3 mg, 2 eq, 3.5 mmol) was added. 1-Bromo-3-methoxypropane (1.1 mL, 4 eq, 7.0 mmol) was added, and the mixture was stirred at 60°C for 1 h. After completion of the reaction, the mixture was cooled to 0°C and water was added to quench the reaction. The organic layer was extracted twice with ethyl acetate, and the organic layer was dried over sodium sulfate. The organic layer was filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by amino silica gel column chromatography (20% EA / Hex) to obtain 2-(2-fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (yellow solid 285 mg, yield 37%). MH + 444.

[0404]

[0405] Step 3: 2-(2-fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (46)

[0406] 2-(2-Fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (285 mg, 1 eq, 0.64 mmol) was dissolved in MeOH (16.1 mL, 0.04 M), titanium(IV) isopropoxide (971.5 μL, 5 eq, 3.21 mmol) and 2 M methylamine in THF (3.2 mL, 10 eq, 6.43 mmol) were added, and the mixture was stirred at room temperature for 10 hours. Sodium borohydride (48.6 mg, 2 eq, 1.29 mmol) was slowly added, and the mixture was stirred for 5 minutes. After the reaction was completed, saturated aqueous NaHCO3 solution was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography (50-100% EA / Hex) to obtain 2-(2-fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (clear gel 163 mg, yield 55%).

[0407] 1 H NMR (500 MHz, DMSO-d6) δ 7.41 - 7.47 (m, 2 H), 7.09 - 7.23 (m, 4 H), 7.03 (dd,J=7.79, 0.92 Hz, 1 H), 6.70 (t,J=2.14 Hz, 1 H), 6.23 (s, 1 H), 3.92 (t,J=6.42 Hz, 2 H), 3.80 - 3.85 (m, 1 H), 3.42 (t,J=6.27 Hz, 2 H), 3.22 (s, 3 H), 2.97 (td,J=4.47, 1.91 Hz, 1 H), 2.77 - 2.87 (m, 1 H), 2.48 - 2.57 (m, 1 H), 2.17 (s, 3 H), 1.97 - 2.05 (m, 1 H), 1.89 (quin,J=6.30 Hz, 2 H); MS m / z 428 (MH + - NH2Me)

[0408]

[0409] Step 4: 2-(2-fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (47)

[0410] 2-(2-Fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (163 mg, 1 eq, 0.36 mmol) was dissolved in ethyl acetate (1.2 mL, 0.3 M) and stirred at 0°C for 2 minutes. 1 M HCl in EA (427 μL, 1.2 eq) was added, and the reaction temperature was slowly raised to room temperature and stirred for 30 minutes. The reaction mixture was concentrated, and the concentrated residue was washed with Hex:Et2O (1:1) solvent and concentrated to obtain 2-(2-fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (brown gel 153 mg, yield 87%).

[0411] 1H NMR (500 MHz, DMSO-d6) δ 8.80 (br s, 1 H), 7.46 - 7.55 (m, 2 H), 7.30 (ddd,J=8.37, 2.56, 0.84 Hz, 1 H), 7.19 - 7.25 (m, 2 H), 7.09 - 7.15 (m, 2 H), 6.75 (t,J=2.3 Hz 1 H), 6.45 (s, 1 H), 4.45 (br d,J=7.64 Hz, 1 H), 3.96 (t,J=6.50 Hz, 2 H), 3.40 - 3.52 (m, 2 H), 3.27 (s, 3 H), 3.16 - 3.26 (m, 1 H), 3.03 (ddd,J=16.51, 9.02, 3.52 Hz, 1 H), 2.80 (dtd,J=14.33, 8.65, 5.81 Hz, 1 H), 2.53 (s, 3 H), 2.36 - 2.43 (m, 1 H), 1.91 - 1.99 (m, 2H); MS m / z 428 (MH + - NH2Me - HCl)

[0412]

[0413] [Example 18] N-Ethyl-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (48)

[0414]

[0415]

[0416] 2-(2-Fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (100 mg, 1.0 eq) was dissolved in dichloromethane (5 mL). Titanium(IV) isopropoxide (0.41 mL, 5 eq) and 2 M EtNH2 (0.2 mL) were added dropwise, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and diluted with methanol (5 mL). After cooling the reaction mixture to 0°C, sodium borohydride (101 mg, 10.0 eq) was slowly added dropwise, and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by adding distilled water, diluted with ethyl acetate, and washed 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 silica gel column chromatography to obtain N-ethyl-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow solid, 30 mg, yield 28%).

[0417] 1 H NMR (500 MHz, DMSO-d6) δ 7.60 - 7.67 (m, 2 H), 7.47 - 7.52 (m, 1 H), 7.31 (dt,J=6.92, 1.81 Hz, 1 H), 7.18 - 7.24 (m, 2 H), 7.10 - 7.17 (m, 2 H), 6.33 (s, 1 H), 3.99 - 4.10 (m, 1 H), 3.02 - 3.12 (m, 1 H), 2.86 - 2.96 (m, 1 H), 2.55 - 2.69 (m, 3 H), 2.07 - 2.17 (m, 1 H), 1.01 (t,J=7.11 Hz, 3 H); MS m / z 358 (MH + - NH2Et)

[0418]

[0419] [Example 19] 2-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (58)

[0420]

[0421]

[0422] Step 1: tert-Butyl 2-bromo-1H-pyrrole-1-carboxylate (10)

[0423] Pyrrole (10.3 mL) was dissolved in THF (300 mL), and N-bromosuccinimide (26.5 g) was added at -78°C and stirred for 5 minutes. The mixture was stirred at -20°C for 5 hours, cooled to -78°C, and filtered under reduced pressure. TEA (41.5 mL), DMAP (364 mg), and di-tert-butyl dicarbonate (51.36 mL) were added to the reaction mixture and stirred at room temperature for 8 hours. EA 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 tert-butyl 2-bromo-1H-pyrrole-1-carboxylate. The synthesized compound was used in the next reaction without any additional purification (black solid, crude). MH + 246

[0424]

[0425] Step 2: 2-(2,4-difluorophenyl)-1H-pyrrole (50)

[0426] tert-Butyl 2-bromo-1H-pyrrole-1-carboxylate (36.7 g) was dissolved in a mixed solvent of toluene (400 mL), H2O (67 mL), and ethanol (67 mL), and then (2,4-difluorophenyl)boronic acid (29.9 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane complex (10.9 g), and potassium carbonate (41.2 g) were added and stirred at 110°C for 16 hours. The reaction solution was cooled to 20-25°C and then filtered through a celite ® It was filtered under reduced pressure and washed with EA. The filtrate was concentrated under reduced pressure, diluted with EA, and washed 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, diluted with THF (400 mL), and 33% sodium methoxide in MeOH (30 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reactant was concentrated under reduced pressure, diluted with EA, and washed 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 2-(2,4-difluorophenyl)-1H-pyrrole. The synthesized compound was used in the next reaction without a separate purification process (black solid, crude).

[0427] 1 H NMR (500 MHz, DMSO-d6) δ 11.23 (br s, 1 H), 7.69 (td,J=9.02, 6.59 Hz, 1 H), 7.25 (ddd,J=11.89, 9.31, 2.29 Hz, 1 H), 7.04 - 7.15 (m, 1 H), 6.83 - 6.92 (m, 1 H), 6.40 - 6.51 (m, 1 H), 6.07 - 6.15 (m, 1 H); MH + 180

[0428]

[0429] Step 3: 5-(2,4-difluorophenyl)-1H-pyrrole-2-carbaldehyde (51)

[0430] 2-(2,4-difluorophenyl)-1H-pyrrole (18.8 g) was dissolved in DMF (120 mL), and POCl3 (14.7 mL) was slowly added dropwise at 0°C. The reaction mixture was stirred at 40°C for 30 minutes. 1 N NaOH aqueous solution (314 mL) was slowly added dropwise and stirred at 110°C for 2 hours. The reaction was quenched by adding distilled water, diluted with EA, and washed 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 silica gel column chromatography to obtain 5-(2,4-difluorophenyl)-1H-pyrrole-2-carbaldehyde (brown solid, 28.1 g, yield 74%).

[0431] 1 H NMR (500 MHz, DMSO-d6) δ 12.36 (br s, 1 H), 9.51 (s, 1 H), 7.88 - 8.01 (m, 1 H), 7.30 - 7.41 (m, 1 H), 7.13 - 7.22 (m, 1 H), 7.07 (d,J=3.44 Hz, 1 H), 6.63 (t,J=3.72 Hz, 1 H); MH + 208

[0432]

[0433] Step 4: Ethyl (E)-3-(5-(2,4-difluorophenyl)-1H-pyrrol-2-yl)acrylate (52)

[0434] Triethyl phosphonoacetate (32.4 mL) and cesium carbonate (66.6 g) were diluted in a mixed solvent of 1,4-dioxane (454 mL) and H2O (4.5 mL) and stirred at room temperature for 30 minutes. 5-(2,4-difluorophenyl)-1H-pyrrole-2-carbaldehyde (28.2 g) was added to the reaction mixture and stirred at 80°C for 24 hours. Distilled water was added to quench the reaction, EA was added, the mixture was diluted, and the mixture was washed 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, washed with petroleum ether, and dried to obtain ethyl (E)-3-(5-(2,4-difluorophenyl)-1H-pyrrol-2-yl)acrylate (brown solid, 35.8 g, yield 95%).

[0435] 1 H NMR (500 MHz, DMSO-d6) δ 11.58 (br s, 1 H), 7.83 (td,J=8.88, 6.87 Hz, 1 H), 7.46 (d,J=15.47 Hz, 1 H), 7.33 (ddd,J=11.74, 9.16, 2.58 Hz, 1 H), 7.19 (td,J=8.59, 2.29 Hz, 1 H), 6.65 - 6.73 (m, 1 H), 6.51 - 6.59 (m, 1 H), 6.40 (d,J=15.46 Hz, 1 H), 4.11 (q,J=7.06 Hz, 2 H), 1.21 (t,J=7.16 Hz, 3 H); MH + 278

[0436]

[0437] Step 5: Ethyl 3-(5-(2,4-difluorophenyl)-1H-pyrrol-2-yl)propanoate (53)

[0438] Ethyl (E)-3-(5-(2,4-difluorophenyl)-1H-pyrrol-2-yl)acrylate (35.8 g) was diluted in DCM (430 mL) and 10% palladium on carbon (4.5 g) was added. The reaction mixture was replaced with hydrogen gas and stirred at room temperature for 24 hours. After completion of the reaction, Celite ® The residue was filtered under reduced pressure and washed with EA. The filtrate was concentrated under reduced pressure to obtain ethyl 3-(5-(2,4-difluorophenyl)-1H-pyrrol-2-yl)propanoate. The synthesized compound was used in the next reaction without any separate purification process (yellow solid, crude).

[0439] 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (br s, 1 H), 7.69 (td,J=8.98, 6.50 Hz, 1 H), 7.25 (ddd,J=11.88, 9.28, 2.67 Hz, 1 H), 7.06 - 7.16 (m, 1 H), 6.35 (q,J=3.36 Hz, 1 H), 5.87 (dd,J=3.21, 2.60 Hz, 1 H), 4.07 (q,J=7.13 Hz, 2 H), 2.81 - 2.90 (m, 2 H), 2.59 - 2.70 (m, 2 H), 1.18 (t,J=7.11 Hz, 3 H); MH + 280

[0440]

[0441] Step 6: 3-(5-(2,4-difluorophenyl)-1H-pyrrol-2-yl)propanoic acid (54)

[0442] Ethyl 3-(5-(2,4-difluorophenyl)-1H-pyrrol-2-yl)propanoate (36.1 g) was dissolved in a mixed solution of THF (344 mL) and H2O (86 mL). Potassium hydroxide (14.5 g) was added and stirred at 80°C for 3 hours. Distilled water was added to stop the reaction, 1N HCl aqueous solution was slowly added dropwise, EA was added, the mixture was diluted, and then washed 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 3-(5-(2,4-difluorophenyl)-1H-pyrrol-2-yl)propanoic acid. The synthesized compound was used in the next reaction without a separate purification process (yellow solid, crude).

[0443] 1 H NMR (500 MHz, DMSO-d6) δ 11.82 - 12.43 (m, 1 H), 10.96 (br s, 1 H), 7.66 (td,J=9.02, 6.57 Hz, 1 H), 7.22 (ddd,J=11.92, 9.32, 2.60 Hz, 1 H), 7.01 - 7.13 (m, 1 H), 6.32 (q,J=3.41 Hz, 1 H), 5.84 (t,J=2.90 Hz, 1 H), 2.78 (t,J=7.72 Hz, 2 H), 2.52 (t,J=7.72 Hz, 2 H); MH + 252

[0444]

[0445] Step 7: 2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (55)

[0446] Polyphosphoric acid (116.4 g) was stirred at 110°C, and 3-(5-(2,4-difluorophenyl)-1H-pyrrol-2-yl)propanoic acid (29.2 g) was slowly added dropwise. The reaction mixture was stirred at 100°C for 30 minutes. After completion of the reaction, MeOH and EA were added, diluted, and washed 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 silica gel column chromatography to obtain 2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (brown solid 21.2 g, yield 78%).

[0447] 1 H NMR (500 MHz, DMSO-d6) δ 11.94 (br s, 1 H), 7.72 (td,J=8.88, 6.30 Hz, 1 H), 7.34 (ddd,J=11.74, 9.16, 2.58 Hz, 1 H), 7.09 - 7.22 (m, 1 H), 6.47 (d,J=2.29 Hz, 1 H), 2.88 - 2.95 (m, 2 H), 2.69 - 2.76 (m, 2 H); MH + 234

[0448]

[0449] Step 8: 2-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (56)

[0450] 2-(2,4-Difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (200 mg) was dissolved in DMF (2.86 mL), and 60% sodium hydride dispersion in mineral oil (82 mg) was added at 0°C. The reaction mixture was purged with nitrogen and stirred at room temperature for 1 h. 3-Fluorobenzenesulfonyl chloride (341 μL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched by adding distilled water at 0°C, and extracted with EA. 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 2-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (yellow solid, 266 mg, yield 79%).

[0451] 1 H NMR (500 MHz, DMSO-d6) δ 7.58 - 7.69 (m, 2 H), 7.35 (dt,J=7.57, 1.57 Hz, 1 H), 7.30 (dt,J=8.06, 2.01 Hz, 1 H), 7.25 (td,J=9.55, 2.45 Hz, 1 H), 7.03 - 7.18 (m, 2 H), 6.50 (s, 1 H), 3.35 (s, 2 H), 2.82 (dt,J=4.85, 2.24 Hz, 2 H); MH + 392

[0452]

[0453] Step 9: 2-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (57)

[0454] 2-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (266 mg) was dissolved in MeOH (17 mL), titanium(IV) isopropoxide (1.02 mL), and 2 M methylamine in THF. (3.4 mL) was added dropwise and stirred at room temperature for 5 hours. After cooling the reaction to 0℃, sodium borohydride (257 mg) was slowly added dropwise and stirred at room temperature for 10 minutes. The reaction was quenched by adding distilled water, diluted with EA, and washed 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 silica gel column chromatography to obtain 2-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow oil 103 mg, yield 37%).

[0455] 1 H NMR (500 MHz, DMSO-d6) δ 7.54 - 7.65 (m, 2 H), 7.21 - 7.31 (m, 2 H), 7.10 - 7.20 (m, 2 H), 7.03 - 7.10 (m, 1 H), 6.29 (s, 1 H), 3.81 - 3.91 (m, 1 H), 2.94 - 3.08 (m, 1 H), 2.77 - 2.90 (m, 1 H), 2.49 - 2.61 (m, 1 H), 2.19 (s, 3 H), 2.03 (ddt,J=13.24, 8.81, 4.41 Hz, 1 H); MH - 405

[0456]

[0457] Step 10: 2-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (58)

[0458] 2-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (50 mg) was dissolved in EA (1.3 mL), and 1 M HCl in EA (0.15 mL) was added. The reaction mixture was stirred at room temperature for 3 h. The resulting solid was filtered through EA to obtain 2-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (40 mg of ivory solid, yield 69%).

[0459] 1 H NMR (500 MHz, DMSO-d6) δ 8.91 (br s, 2 H), 7.58 - 7.66 (m, 2 H), 7.24 - 7.34 (m, 2 H), 7.17 - 7.23 (m, 1 H), 7.05 - 7.15 (m, 2 H), 6.46 (s, 1 H), 4.42 (br d,J=7.49 Hz, 1 H), 3.13 - 3.22 (m, 1 H), 3.03 (ddd,J=16.58, 9.02, 3.44 Hz, 1 H), 2.77 (dtd,J=14.31, 8.74, 5.96 Hz, 1 H), 2.50 (s, 3 H), 2.39 (ddt,J=14.50, 8.31, 3.04 Hz, 1 H); MS m / z 405 (MH - - HCl)

[0460]

[0461] [Example 20] 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (60)

[0462]

[0463]

[0464] Step 1: 2-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (59)

[0465] 2-(2,4-Difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (3 g) was dissolved in THF (43 mL), and a 60% sodium hydride dispersion in mineral oil (1.03 g) was added at 0°C. The reaction mixture was purged with nitrogen and stirred at room temperature for 1 h. Pyridine-3-sulfonyl chloride (1.98 mL) was added, and the mixture was stirred at room temperature for 16 h. The reaction was quenched by adding distilled water at 0°C, and extracted with EA. 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 2-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (yellow solid 2.77 g, yield 58%).

[0466] 1 H NMR (500 MHz, DMSO-d6) δ 8.90 (dd,J=4.81, 1.45 Hz, 1 H), 8.59 (dd,J=2.45, 0.61 Hz, 1 H), 7.94 (ddd,J=8.21, 2.56, 1.60 Hz, 1 H), 7.61 (ddd,J=8.25, 4.89, 0.76 Hz, 1 H), 7.26 (td,J=9.59, 2.37 Hz, 1 H), 7.03 - 7.18 (m, 2 H), 6.51 (s, 1 H), 3.32 - 3.35 (m, 2 H), 2.83 (dt,J=4.85, 2.24 Hz, 2 H); MH + 375

[0467]

[0468] Step 2: 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (60)

[0469] 2-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (7.1 g) was dissolved in DCM (317 mL) and titanium(IV) isopropoxide (17.1 mL), 2 M methylamine (47.66 mL) was added dropwise and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with MeOH (190 mL). After cooling the reaction mixture to 0℃, sodium borohydride (3.6 g) was slowly added dropwise and stirred at room temperature for 1 hour. The reaction mixture was quenched by adding distilled water, diluted with EA, and washed 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 silica gel column chromatography to obtain 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow oil 4.9 g, yield 64%).

[0470] 1 H NMR (500 MHz, DMSO-d6) δ 8.84 (dd,J=4.74, 1.53 Hz, 1 H), 8.49 (dd,J=2.45, 0.61 Hz, 1 H), 7.81 (ddd,J=8.14, 2.48, 1.60 Hz, 1 H), 7.59 (ddd,J=8.18, 4.81, 0.76 Hz, 1 H), 7.25 (td,J=9.67, 2.52 Hz, 1 H), 7.16 (td,J=8.44, 6.65 Hz, 1 H), 7.07 (td,J=8.48, 2.29 Hz, 1 H), 6.30 (s, 1 H), 3.83 (dt,J=4.58, 2.90 Hz, 1 H), 2.95 - 3.07 (m, 1 H), 2.86 (ddd,J=16.28, 8.86, 4.97 Hz, 1 H), 2.50 - 2.60 (m, 1 H), 2.18 (s, 3 H), 1.98 - 2.08 (m, 1 H); MH - 388

[0471]

[0472] [Example 21] 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine fumarate (61)

[0473]

[0474]

[0475] 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (600 mg) was dissolved in EA (7.7 mL), and fumaric acid (196 mg) was added. The reaction mixture was stirred at room temperature for 3 hours. The resulting solid was filtered with a mixed solution of EA and hexane to obtain 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine fumarate (ivory solid, 710 mg, yield 91%).

[0476] 1 H NMR (500 MHz, DMSO-d6) δ 8.86 (dd,J=4.74, 1.53 Hz, 1 H), 8.52 (dd,J=2.45, 0.61 Hz, 1 H), 7.84 (ddd,J=8.18, 2.52, 1.53 Hz, 1 H), 7.59 (ddd,J=8.18, 4.81, 0.76 Hz, 1 H), 7.26 (td,J=9.63, 2.45 Hz, 1 H), 7.03 - 7.17 (m, 2 H), 6.41 (s, 2 H), 6.40 (s, 1 H), 4.19 - 4.28 (m, 1 H), 3.08 - 3.18 (m, 2 H), 2.99 (ddd,J=16.66, 9.09, 3.74 Hz, 2 H), 2.70 (dtd,J=13.85, 8.51, 5.65 Hz, 1 H), 2.39 (s, 3 H), 2.23 - 2.35 (m, 1 H); MS m / z 388 (MH - - C4H4O4)

[0477]

[0478] [Example 22] 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride (62)

[0479]

[0480]

[0481] 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (101 mg) was dissolved in EA (1.3 mL), and 1 M HCl in EA (0.57 mL) was added. The reaction was stirred at room temperature for 3 h. The resulting solid was filtered with EA to obtain 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride (101 mg of ivory solid, yield 92%).

[0482] 1 H NMR (500 MHz, DMSO-d6) δ 8.89 - 8.98 (m, 2 H), 8.88 (dd,J=4.89, 1.53 Hz, 1 H), 8.50 - 8.56 (m, 1 H), 8.10 (s, 1 H), 7.86 (ddd,J=8.21, 2.48, 1.53 Hz, 1 H), 7.60 (ddd,J=8.18, 4.81, 0.76 Hz, 1 H), 7.27 (td,J=9.59, 1.76 Hz, 1 H), 7.04 - 7.16 (m, 2 H), 6.47 (s, 1 H), 4.43 (br dd,J=4.89, 1.83 Hz, 1 H), 3.13 - 3.27 (m, 1 H), 3.00 - 3.10 (m, 1 H), 2.78 (dtd,J=14.33, 8.62, 5.58 Hz, 1 H), 2.51 (t,J=5.43 Hz, 3 H), 2.35 - 2.44 (m, 1 H); MS m / z 388 (MH -- 2HCl)

[0483]

[0484] [Example 23] 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (2E,4E)-hexa-2,4-dienoate (63)

[0485]

[0486]

[0487] 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (100 mg, 1 eq) was dissolved in ethyl acetate (1 mL, 10 v / w), sorbic acid (31.7 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 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (2E,4E)-hexa-2,4-dienoate (white solid 90 mg, yield 65.4%).

[0488] 1H NMR (500 MHz, DMSO-d6) δ 8.88 (dd,J=4.74, 1.53 Hz, 1 H), 8.53 (d,J=2.45 Hz, 1 H), 7.83 - 7.87 (m, 1 H), 7.62 (ddd,J=8.18, 4.81, 0.76 Hz, 1 H), 7.28 (td,J=9.63, 2.45 Hz, 1 H), 7.19 (td,J=8.44, 6.65 Hz, 1 H), 7.06 - 7.13 (m, 2 H), 6.35 (s, 1 H), 6.12 - 6.28 (m, 2 H), 5.75 (d,J=15.28 Hz, 1 H), 4.03 (q,J=7.13 Hz, 1 H), 3.91 - 3.95 (m, 1 H), 3.02 - 3.11 (m, 1 H), 2.92 (ddd,J=16.35, 8.94, 4.81 Hz, 1 H), 2.60 (dtd,J=13.05, 8.42, 4.97 Hz, 1 H), 2.24 (s, 3 H), 2.10 (ddt,J=13.24, 8.77, 4.51 Hz, 1 H), 1.99 (s, 1 H), 1.80 (d,J=6.57 Hz, 3 H), 1.17 (t,J=7.18 Hz, 1 H); MS m / z 359 (MH + - NH2Me - C6H8O2)

[0489]

[0490] [Example 24] 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine adipate (64)

[0491]

[0492]

[0493] 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (100 mg, 1 eq) was dissolved in ethyl acetate (1 mL, 10 v / w), adipic acid (41.3 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 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine adipate (90 mg of white solid, yield 65.4%).

[0494] 1 H NMR (500 MHz, DMSO-d6) δ 8.88 (dd,J=4.81, 1.45 Hz, 1 H), 8.53 (dd,J=2.45, 0.61 Hz, 1 H), 7.85 (ddd,J=8.14, 2.48, 1.60 Hz, 1 H), 7.62 (ddd,J=8.18, 4.81, 0.76 Hz, 1 H), 7.28 (td,J=9.67, 2.52 Hz, 1 H), 7.19 (td,J=8.44, 6.65 Hz, 1 H), 7.08 - 7.14 (m, 1 H), 6.36 (s, 1 H), 4.03 (q,J=7.03 Hz, 1 H), 3.95 - 3.99 (m, 1 H), 3.04 - 3.12 (m, 1 H), 2.93 (ddd,J=16.39, 8.98, 4.74 Hz, 1 H), 2.62 (dtd,J=13.12, 8.49, 5.04 Hz, 1 H), 2.26 (s, 3 H), 2.15 - 2.19 (m, 4 H), 2.10 - 2.15 (m, 1 H), 1.99 (s, 1 H), 1.45 - 1.51 (m, 4 H), 1.17 (t,J=7.11 Hz, 1 H); MS m / z 359 (MH + - NH2Me - C6H 10 O4)

[0495]

[0496] [Example 25] 1-((3-chlorophenyl)sulfonyl)-2-(2,4-difluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (67)

[0497]

[0498]

[0499] Step 1: 1-((3-chlorophenyl)sulfonyl)-2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (65)

[0500] 2-(2,4-Difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (200 mg) was dissolved in DMF (4.3 mL), and a 60% sodium hydride dispersion in mineral oil (52 mg) was added at 0°C. The reaction mixture was purged with nitrogen and stirred at room temperature for 1 h. 3-Chlorobenzenesulfonyl chloride (133 μL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched by adding distilled water at 0°C, and extracted with EA. 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-chlorophenyl)sulfonyl)-2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (yellow solid, 200 mg, yield 57%).

[0501] 1 H NMR (500 MHz, Methanol-d4) δ 7.70 - 7.75 (m, 1 H), 7.52 - 7.54 (m, 2 H), 7.28 - 7.32 (m, 1 H), 7.14 (td,J=8.41, 6.42 Hz, 1 H), 6.90 - 7.02 (m, 2 H), 6.35 (s, 1 H), 3.38 - 3.44 (m, 2 H), 2.90 - 2.97 (m, 2 H); MH + 408

[0502]

[0503] Step 2: 1-((3-chlorophenyl)sulfonyl)-2-(2,4-difluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (66)

[0504] 1-((3-Chlorophenyl)sulfonyl)-2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (200 mg) was dissolved in MeOH (12.3 mL), and titanium(IV) isopropoxide (735 μL) and 2 M methylamine in THF (2.45 mL) were added dropwise, followed by stirring at room temperature for 5 hours. The reaction mixture was cooled to 0°C, and sodium borohydride (185 mg) was slowly added dropwise, followed by stirring at room temperature for 10 minutes. The reaction was quenched by adding distilled water, diluted with EA, and washed 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 silica gel column chromatography to obtain 1-((3-chlorophenyl)sulfonyl)-2-(2,4-difluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow oil 81.6 mg, yield 41%).

[0505] 1 H NMR (500 MHz, Methanol-d4) δ 7.63 - 7.69 (m, 1 H), 7.45 - 7.52 (m, 1 H), 7.39 - 7.44 (m, 1 H), 7.27 (t,J=1.91 Hz, 1 H), 7.08 - 7.16 (m, 1 H), 6.89 - 6.99 (m, 2 H), 6.26 (s, 1 H), 4.09 - 4.12 (m, 1 H), 3.12 - 3.24 (m, 1 H), 2.98 - 3.08 (m, 1 H), 2.72 - 2.81 (m, 1 H), 2.40 (s, 3) H), 2.24 (ddt,J=13.35, 8.92, 4.22 Hz, 1 H); MH - 421

[0506]

[0507] Step 3: 1-((3-chlorophenyl)sulfonyl)-2-(2,4-difluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (67)

[0508] 1-((3-Chlorophenyl)sulfonyl)-2-(2,4-difluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (85 mg) was dissolved in EA (2 mL), and 1 M HCl in EA (0.3 mL) was added. The reaction mixture was stirred at room temperature for 3 h. The resulting solid was filtered through EA to obtain 1-((3-chlorophenyl)sulfonyl)-2-(2,4-difluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (45 mg of ivory solid, yield 49%).

[0509] 1 H NMR (500 MHz, DMSO-d6) δ 8.90 (br s, 1 H), 7.82 (ddd,J=8.10, 1.99, 0.76 Hz, 1 H), 7.59 (t,J=8.02 Hz, 1 H), 7.44 - 7.50 (m, 1 H), 7.23 - 7.31 (m, 2 H), 7.06 - 7.16 (m, 2 H), 6.46 (s, 1 H), 4.43 (br d,J=7.49 Hz, 1 H), 3.13 - 3.23 (m, 1 H), 3.04 (ddd,J=16.54, 9.21, 3.44 Hz, 1 H), 2.78 (dtd,J=14.44, 8.75, 5.65 Hz, 1 H), 2.50 (s, 3 H), 2.39 (ddt,J=14.46, 8.08, 3.17 Hz, 1 H); MS m / z 421 (MH - - HCl)

[0510]

[0511] [Example 26] 2-(2,4-difluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (70)

[0512]

[0513]

[0514] Step 1: 2-(2,4-difluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (68)

[0515] 2-(2,4-Difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (576 mg) was dissolved in DMF (12.4 mL), and a 60% sodium hydride dispersion in mineral oil (148 mg) was added at 0°C. The reaction mixture was purged with nitrogen and stirred at room temperature for 1 h. 3-Methoxybenzenesulfonyl chloride (428 μL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched by adding distilled water at 0°C, and extracted with EA. 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 2-(2,4-difluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (yellow solid 876 mg, yield 88%).

[0516] 1 H NMR (500 MHz, DMSO-d6) δ 7.44 - 7.53 (m, 1 H), 7.22 - 7.35 (m, 2 H), 7.05 - 7.20 (m, 3 H), 6.81 (t,J=2.14 Hz, 1 H), 6.47 (s, 1 H), 3.72 (s, 3 H), 3.28 (dt,J=4.74, 2.22 Hz, 2 H), 2.82 (dt,J=4.81, 2.18 Hz, 2 H); MH + 404

[0517]

[0518] Step 2: 2-(2,4-difluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (69)

[0519] 2-(2,4-difluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (875 mg) was dissolved in MeOH (50 mL) and titanium(IV) isopropoxide (3.2 mL), 2 M methylamine in THF (10.9 mL) was added dropwise and stirred at room temperature for 5 hours. After cooling the reaction to 0℃, sodium borohydride (821 mg) was slowly added dropwise and stirred at room temperature for 10 minutes. The reaction was quenched by adding distilled water, diluted with EA, and washed 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 silica gel column chromatography to obtain 2-(2,4-difluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow oil 251 mg, yield 28%).

[0520] 1 H NMR (500 MHz, DMSO-d6) δ 7.46 (t,J=8.10 Hz, 1 H), 7.20 - 7.29 (m, 2 H), 7.12 - 7.20 (m, 1 H), 7.01 - 7.10 (m, 2 H), 6.72 - 6.76 (m, 1 H), 6.25 (s, 1 H), 3.79 - 3.86 (m, 1 H), 3.71 (s, 3 H), 2.94 - 3.03 (m, 1 H), 2.81 (ddd,J=16.12, 8.94, 5.04 Hz, 1 H), 2.48 - 2.58 (m, 1 H), 2.18 (s, 3 H), 1.97 - 2.06 (m, 1 H); MH - 416

[0521]

[0522] Step 3: 2-(2,4-difluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (70)

[0523] 2-(2,4-difluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (251 mg) was dissolved in EA (6 mL), and 1 M HCl in EA (0.9 mL) was added. The reaction mixture was stirred at room temperature for 3 h. The resulting solid was filtered through EA to obtain 2-(2,4-difluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (ivory solid, 189 mg, yield 69%).

[0524] 1 H NMR (500 MHz, DMSO-d6) δ 8.82 (br d,J=5.04 Hz, 1 H), 7.48 (t,J=8.10 Hz, 1 H), 7.24 - 7.32 (m, 2 H), 7.05 - 7.18 (m, 3 H), 6.77 (t,J=2.14) Hz, 1 H), 6.43 (s, 1 H), 4.42 (br d,J=7.49 Hz, 1 H), 3.72 (s, 3 H), 3.10 - 3.21 (m, 1 H), 2.99 (ddd,J=16.70, 9.06, 3.44 Hz, 1 H), 2.76 (dtd,J=14.35, 8.68, 5.43 Hz, 1 H), 2.49 (s, 3 H), 2.30 - 2.41 (m, 1 H); MS m / z 416 (MH - - HCl)

[0525]

[0526] [Example 27] 3-((2-(2,4-difluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)phenol hydrochloride (72)

[0527]

[0528]

[0529] Step 1: 3-((2-(2,4-difluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)phenol (71)

[0530] 2-(2,4-difluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (180 mg) was dissolved in DCM (4.3 mL), and 1 M borotribromide solution (1.29 mL) was slowly added dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 h. After cooling to 0°C, MeOH and distilled water were added, and 1 N NaOH aqueous solution was slowly added dropwise. EA was added to dilute, and the organic layer was extracted, 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-((2-(2,4-difluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)phenol (83 mg of clear oil, yield 47%). MH - 403

[0531]

[0532] Step 2: 3-((2-(2,4-difluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)phenol hydrochloride (72)

[0533] 3-((2-(2,4-difluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)sulfonyl)phenol (81 mg) was dissolved in EA (2 mL), and 1 M HCl in EA (0.3 mL) was added. The reaction was stirred at room temperature for 3 h. The resulting solid was filtered with EA to obtain 3-((2-(2,4-difluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)sulfonyl)phenol hydrochloride (ivory solid, 30 mg, yield 37%).

[0534] 1 H NMR (500 MHz, DMSO-d6) δ 10.32 (br s, 1 H), 8.68 (br s, 1 H), 7.33 (t,J=8.02 Hz, 1 H), 7.24 (td,J=9.55, 2.45 Hz, 1 H), 7.02 - 7.15 (m, 3 H), 6.82 - 6.89 (m, 1 H), 6.76 (t,J=2.14 Hz, 1 H), 6.37 (s, 1 H), 4.29 (br s, 1 H), 3.04 - 3.14 (m, 1 H), 2.93 (ddd,J=16.54, 9.21, 3.74 Hz, 1 H), 2.72 (dtd,J=14.18, 8.54, 8.54, 5.58 Hz, 1 H), 2.44 (s, 3 H), 2.23 - 2.31 (m, 1 H); MS m / z 403 (MH - - HCl)

[0535]

[0536] [Example 28] 3-((2-(2,4-difluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)benzonitrile (75)

[0537]

[0538]

[0539] Step 1: 3-((2-(2,4-difluorophenyl)-4-oxo-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)benzonitrile (74)

[0540] 2-(2,4-Difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (150 mg, 1 eq, 0.643 mmol) was dissolved in THF (2.1 mL, 0.3 M) and stirred for 5 minutes under nitrogen at 0°C. A 60% sodium hydride dispersion in mineral oil (51.5 mg, 2 eq, 1.29 mmol) was added and stirred for 1 hour. 3-Cyanobenzenesulfonyl chloride (142.6 mg, 1.1 eq, 0.71 mmol) was added and stirred at room temperature for 30 minutes. After completion of the reaction, NaHCO3(aq) was added at 0°C to terminate the reaction and extracted twice with ethyl acetate. Sodium sulfate was added to the organic layer, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by normal silica gel column chromatography (50-100% EA / Hex) to obtain 3-((2-(2,4-difluorophenyl)-4-oxo-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)benzonitrile (brown solid 144 mg, yield 56%).

[0541] 1 H NMR (500 MHz, DMSO-d6) δ 8.26 (dt,J=7.34, 1.53 Hz, 1 H), 7.96 (t,J=1.45 Hz, 1 H), 7.75 - 7.84 (m, 2 H), 7.28 (td,J=9.55, 2.60 Hz, 1 H), 7.06 - 7.18 (m, 2 H), 6.55 (s, 1 H), 3.35 - 3.39 (m, 2 H), 2.84 - 2.89 (m, 2 H); MH + 399

[0542]

[0543] Step 2: 3-((2-(2,4-difluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)benzonitrile (75)

[0544] 3-((2-(2,4-difluorophenyl)-4-oxo-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)benzonitrile (144 mg, 1 eq, 0.36 mmol) was dissolved in DCM (9.0 mL, 0.04 M), titanium(IV) isopropoxide (327.9 μL, 3 eq, 1.08 mmol) and 2 M methylamine in THF (3.6 mL, 5 eq, 1.81 mmol) were added, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated, and MeOH (3.6 mL, 0.1 M) was added, followed by slow addition of sodium borohydride (41.0 mg, 3 eq, 1.08 mmol) at 0°C and stirring for 5 min. After the reaction was completed, saturated aqueous NaHCO3 solution was added to terminate the reaction, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by amino silica gel column chromatography (50-100% EA / Hex) to obtain 3-((2-(2,4-difluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)benzonitrile (orange sticky solid 92 mg, yield 68%).

[0545] 1H NMR (500 MHz, DMSO-d6) δ 8.21 (dt,J=7.68, 1.36 Hz, 1 H), 7.75 - 7.80 (m, 2 H), 7.69 - 7.74 (m, 1 H), 7.28 (td,J=9.63, 2.60 Hz, 1 H), 7.17 (td,J=8.41, 6.72 Hz, 1 H), 7.07 - 7.12 (m, 1 H), 6.33 (s, 1 H), 3.83 - 3.93 (m, 1 H), 3.02 - 3.11 (m, 1 H), 2.91 (ddd,J=16.28, 9.02, 4.97 Hz, 1 H), 2.54 - 2.61 (m, 1 H), 2.22 (s, 3 H), 2.07 (tt,J=8.79, 4.43 Hz, 1 H); MS m / z 383 (MH + - NH2Me)

[0546]

[0547] [Example 29] 2-(2,4-difluorophenyl)-N-methyl-1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (78)

[0548]

[0549]

[0550] Step 1: 2-(2,4-difluorophenyl)-1-((1-methyl-1H-indol-4-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (77)

[0551] 2-(2,4-Difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (200 mg) was dissolved in THF (4.3 mL), and 60% sodium hydride dispersion in mineral oil (52 mg) was added at 0°C. The reaction mixture was purged with nitrogen and stirred at room temperature for 1 hour. 1-Methyl-1H-indole-4-sulfonyl chloride (217.3 mg) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding distilled water at 0°C, and extracted with EA. 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 2-(2,4-difluorophenyl)-1-((1-methyl-1H-indol-4-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (yellow solid, 267 mg, yield 73%).

[0552] 1 H NMR (500 MHz, DMSO-d6) δ 7.08 (d,J=8.25 Hz, 1 H), 6.76 (d,J=3.06 Hz, 1 H), 6.23 - 6.40 (m, 3 H), 6.05 - 6.18 (m, 2 H), 5.55 (s, 1 H), 5.49 (dd,J=3.13, 0.84 Hz, 1 H), 3.03 (s, 3 H), 2.53 (s, 2 H), 2.06 (s, 1 H), 2.03 (dt,J=4.85, 2.24 Hz, 2 H), 1.68 - 1.71 (m, 2 H), 0.34 (t,J=7.11 Hz, 1 H); MH + 427

[0553]

[0554] Step 2: 2-(2,4-difluorophenyl)-N-methyl-1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (78)

[0555] 2-(2,4-difluorophenyl)-1-((1-methyl-1H-indol-4-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (267 mg) was dissolved in DCM (10.5 mL) and titanium(IV) isopropoxide (563 μL), 2 M methylamine (1.58 mL) was added dropwise and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with MeOH (6.3 mL). After cooling the reaction mixture to 0°C, sodium borohydride (119 mg) was slowly added dropwise and stirred at room temperature for 1 hour. The reaction mixture was quenched by adding distilled water, diluted with EA, and washed 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 silica gel column chromatography to obtain 2-(2,4-difluorophenyl)-N-methyl-1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow powder 168 mg, yield 60%).

[0556] 1 H NMR (500 MHz, DMSO-d6) δ 7.83 (d,J=8.25 Hz, 1 H), 7.54 (d,J=3.21 Hz, 1 H), 7.13 - 7.21 (m, 2 H), 6.96 - 7.06 (m, 3 H), 6.32 (dd,J=3.13, 0.84 Hz, 1 H), 6.20 (s, 1 H), 3.94 (br s, 1 H), 3.84 (s, 3 H), 2.99 - 3.11 (m, 1 H), 2.87 (ddd,J=16.16, 8.98, 4.81 Hz, 1 H), 2.54 - 2.66 (m, 1 H), 2.27 (s, 3 H), 2.08 (ddt,J=13.26, 8.75, 4.43 Hz, 1 H); MS m / z 412 (MH + - NH2Me)

[0557]

[0558] [Example 30] 2-(2,4-difluorophenyl)-N-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (81)

[0559]

[0560]

[0561] Step 1: 2-(2,4-difluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (80)

[0562] A 60% sodium hydride dispersion (51 mg, 1.5 eq) in mineral oil was dissolved in THF (2.86 mL, 0.3 M), 2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (200 mg, 1 eq) was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. 3-(Trifluoromethyl)benzenesulfonyl chloride (0.15 mL, 1.1 eq) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched by adding distilled water, 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 2-(2,4-difluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (brown solid, 280 mg, yield 73%).

[0563] 1H NMR (500 MHz, Methanol-d4) δ 8.06 (dt,J=7.87, 0.73 Hz, 1 H), 7.96 (d,J=8.10 Hz, 1 H), 7.78 - 7.84 (m, 1 H), 7.57 (s, 1 H), 7.16 (td,J=8.37, 6.34 Hz, 1 H), 6.97 (tdd,J=8.39, 2.56, 0.99 Hz, 1 H), 6.92 (td,J=9.32, 2.60 Hz, 1 H), 6.39 (s, 1 H), 3.43 - 3.49 (m, 2 H), 2.95 - 3.00 (m, 2 H); MH + 442

[0564]

[0565] Step 2: 2-(2,4-difluorophenyl)-N-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (81)

[0566] 2-(2,4-difluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (270 mg, 1 eq) was dissolved in DCM (15.3 mL, 0.04 M), titanium isopropoxide (0.55 mL, 3 eq) and a 2 M methylamine solution in THF (1.53 mL, 5 eq) were added, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, re-dissolved in MeOH (6.12 mL, 0.1 M), NaBH4 (69 mg, 3 eq) was added, and the mixture was stirred at room temperature for 15 min. The reaction was quenched by adding distilled water, diluted with ethyl acetate, washed several times with distilled water, and rinsed 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 2-(2,4-difluorophenyl)-N-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (brown solid, 232 mg, yield 83%).

[0567] 1 H NMR (500 MHz, Methanol-d4) δ 8.00 (dd,J=7.79, 0.61 Hz, 1 H), 7.81 - 7.85 (m, 1 H), 7.74 - 7.79 (m, 1 H), 7.55 (s, 1 H), 7.11 - 7.18 (m, 1 H), 6.90 - 6.99 (m, 2 H), 6.30 (s, 1 H), 4.11 - 4.16 (m, 1 H), 3.19 - 3.28 (m, 1 H), 3.04 - 3.12 (m, 1 H), 2.76 - 2.85 (m, 1 H), 2.43 (s, 3) H), 2.24 - 2.32 (m, 1 H); MS m / z 426 (MH + - NH2Me)

[0568]

[0569] [Example 31] 2-(2,4-difluorophenyl)-1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (84)

[0570]

[0571]

[0572] Step 1: 2-(2,4-difluorophenyl)-1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (83)

[0573] A 60% sodium hydride dispersion in mineral oil (51 mg, 1.5 eq) was dissolved in THF (2.86 mL, 0.3 M), 2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (200 mg, 1 eq) was added, and the mixture was stirred at room temperature for 2 hours. 2,3-Dihydrobenzo[b][1,4]dioxine-6-sulfonyl chloride (221 mg, 1.1 eq) was added, and the mixture was stirred at room temperature for 18 hours. The reaction was quenched by adding distilled water, 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 2-(2,4-difluorophenyl)-1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (ivory solid, 135 mg, 35%).

[0574] 1H NMR (500 MHz, Methanol-d4) δ 7.17 (td,J=8.48, 6.42 Hz, 1 H), 7.04 (dd,J=8.71, 2.29 Hz, 1 H), 6.95 - 7.01 (m, 2 H), 6.94 (d,J=8.56 Hz, 1 H), 6.86 (d,J=2.45 Hz, 1 H), 6.32 (s, 1 H), 4.32 - 4.36 (m, 2 H), 4.29 (td,J=3.63, 1.91 Hz, 2 H), 3.36 - 3.41 (m, 2 H), 2.92 - 2.96 (m, 2) H); MH + 432

[0575]

[0576] Step 2: 2-(2,4-difluorophenyl)-1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (84)

[0577] 2-(2,4-Difluorophenyl)-1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (130 mg, 1 eq) was dissolved in DCM (7.53 mL, 0.04 M), titanium isopropoxide (0.27 mL, 3 eq) and a 2 M solution of methylamine in THF (0.75 mL, 5 eq) were added, and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, re-dissolved in MeOH (3.01 mL, 0.1 M), NaBH4 (34 mg, 3 eq) was added, and the mixture was stirred at room temperature for 30 min. The reaction was stopped by adding distilled water, 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, purified by amino silica gel column chromatography, and further purified by acid-base workup with 1 N HCl aqueous solution and 1 N NaOH aqueous solution to obtain 2-(2,4-difluorophenyl)-1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (orange sticky oil 32 mg, yield 23%).

[0578] 1H NMR (500 MHz, Methanol-d4) δ 7.16 (td,J=8.41, 6.57 Hz, 1 H), 6.92 - 6.98 (m, 3 H), 6.88 - 6.91 (m, 1 H), 6.84 (d,J=2.29 Hz, 1 H), 6.22 (s, 1 H), 4.29 - 4.33 (m, 2 H), 4.25 - 4.28 (m, 2 H), 4.05 (ddd,J=7.60, 3.78, 1.45 Hz, 1 H), 3.13 - 3.21 (m, 1 H), 3.00 (ddd,J=16.54, 8.98, 4.59 Hz, 1 H), 2.70 - 2.79 (m, 1 H), 2.40 (s, 3 H), 2.22 (ddt,J=13.26, 8.83, 4.39 Hz, 1 H); MS m / z 416 (MH + - NH2Me)

[0579]

[0580] [Example 32] 2-(2,4-difluorophenyl)-1-(furan-2-ylsulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (87)

[0581]

[0582]

[0583] Step 1: 2-(2,4-difluorophenyl)-1-(furan-2-ylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (86)

[0584] A 60% sodium hydride dispersion (51 mg, 1.5 eq) in mineral oil was dissolved in THF (2.86 mL, 0.3 M), 2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (200 mg, 1 eq) was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Furan-2-sulfonyl chloride (0.11 mL, 1.1 eq) was added, and the mixture was stirred at room temperature for 50 minutes. The reaction was quenched by adding distilled water, 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 2-(2,4-difluorophenyl)-1-(furan-2-ylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (brown solid, 143 mg, 45%).

[0585] 1 H NMR (500 MHz, Methanol-d4) δ 7.86 (dd,J=1.83, 0.92 Hz, 1 H), 7.22 - 7.29 (m, 1 H), 6.97 - 7.04 (m, 3 H), 6.64 (dd,J=3.67, 1.83 Hz, 1 H), 6.40 (s, 1 H), 3.35 - 3.38 (m, 2 H), 2.93 - 2.98 (m, 2 H); MH + 364

[0586]

[0587] Step 2: 2-(2,4-difluorophenyl)-1-(furan-2-ylsulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (87)

[0588] 2-(2,4-Difluorophenyl)-1-(furan-2-ylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (140 mg, 1 eq) was dissolved in DCM (9.63 mL, 0.04 M), titanium isopropoxide (0.35 mL, 3 eq) and a 2 M methylamine solution in THF (0.96 mL, 5 eq) were added, and the mixture was stirred at room temperature for 2 h 30 min. The reaction solution was concentrated under reduced pressure, re-dissolved in MeOH (3.85 mL, 0.1 M), NaBH4 (44 mg, 3 eq) was added, and the mixture was stirred at room temperature for 40 min. The reaction was quenched by adding distilled water, diluted with ethyl acetate, washed several times with distilled water, and rinsed 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 amino silica gel column chromatography to obtain 2-(2,4-difluorophenyl)-1-(furan-2-ylsulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (brown sticky gum 113 mg, yield 77%).

[0589] 1 H NMR (500 MHz, Methanol-d4) δ 7.75 (dd,J=1.83, 0.92 Hz, 1 H), 7.19 - 7.26 (m, 1 H), 6.92 - 6.99 (m, 2 H), 6.89 (dd,J=3.59, 0.84 Hz, 1 H), 6.57 (dd,J=3.59, 1.76 Hz, 1 H), 6.28 (s, 1 H), 4.05 (ddd,J=7.64, 3.97, 1.38 Hz, 1 H), 3.11 - 3.19 (m, 1 H), 2.98 (ddd,J=16.58, 9.02, 4.66 Hz, 1 H), 2.74 (dddd,J=13.72, 8.98, 7.79, 4.97 Hz, 1 H), 2.39 (s, 3 H), 2.16 - 2.26 (m, 1 H); MS m / z 348 (MH + - NH2Me)

[0590]

[0591] [Example 33] 2-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (90)

[0592]

[0593]

[0594] Step 1: 2-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (89)

[0595] 2-(2,4-Difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (400 mg, 1.0 eq) was dissolved in THF (10 mL), and a 60% sodium hydride dispersion in mineral oil (82 mg, 2.0 eq) was added at 0°C. The reaction mixture was stirred at room temperature for 1 h. 6-Methoxypyridine-3-sulfonyl chloride (534 mg, 1.5 eq) was added, and the mixture was stirred at room temperature for 16 h. Distilled water was added at 0°C to quench the reaction, EA was added, and the organic layer was extracted 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 silica gel column chromatography to obtain 2-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (brown solid, 380 mg, yield 60%). MH + 405

[0596]

[0597] Step 2: 2-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (90)

[0598] 2-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (120 mg, 1.0 eq) was dissolved in DCM (6 mL) and titanium(IV) isopropoxide (0.45 mL, 5 eq), 2 M methylamine (0.3 mL, 2.0 eq) was added dropwise and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with methanol (10 mL). After cooling the reaction mixture to 0°C, sodium borohydride (112 mg, 10.0 eq) was slowly added dropwise and stirred at room temperature for 1 hour. The reaction mixture was quenched by adding distilled water, diluted with ethyl acetate, and washed 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 silica gel column chromatography to obtain 2-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (viscous liquid 66 mg, yield 53%).

[0599] 1 H NMR (500 MHz, DMSO-d6) δ 8.18 (d,J=2.60 Hz, 1 H), 7.66 (dd,J=8.86, 2.60 Hz, 1 H), 7.28 (td,J=9.63, 2.60 Hz, 1 H), 7.22 (td,J=8.48, 6.72 Hz, 1 H), 7.11 (td, J=8.48, 2.60 Hz, 1 H), 6.96 (dd,J=8.86, 0.61 Hz, 1 H), 6.30 (s, 1 H), 3.93 (s, 3 H), 3.84 - 3.88 (m, 1 H), 2.99 - 3.07 (m, 1 H), 2.89 (br dd,J=9.02, 5.04 Hz, 1 H), 2.52 - 2.65 (m, 2 H), 2.23 (s, 3 H), 2.02 - 2.09 (m, 1 H); MS m / z 389 (MH + - NH2Me)

[0600]

[0601] [Example 34] 2-(2,4-difluorophenyl)-N-methyl-1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (93)

[0602]

[0603]

[0604] Step 1: 2-(2,4-difluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (92)

[0605] 2-(2,4-Difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (200 mg, 1 eq, 0.858 mmol) was dissolved in THF (2.9 mL, 0.3 M) and stirred for 5 minutes under nitrogen at 0°C. A 60% sodium hydride dispersion in mineral oil (51.5 mg, 1.5 eq, 1.29 mmol) was added and stirred for 1 hour. 6-Methylpyridine-3-sulfonyl chloride (180.7 mg, 1.21 eq, 0.94 mmol) was added and stirred at room temperature for 30 minutes. After completion of the reaction, NaHCO3(aq) was added at 0°C to terminate the reaction and extracted twice with ethyl acetate. Sodium sulfate was added to the organic layer, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by normal silica gel column chromatography (50-100% EA / Hex) to obtain 2-(2,4-difluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (brown solid, 240 mg, yield 70%).

[0606] 1H NMR (500 MHz, DMSO-d6) δ 8.47 (d,J=2.60 Hz, 1 H), 7.85 (dd,J=8.25, 2.60 Hz, 1 H), 7.50 (d,J=8.41 Hz, 1 H), 7.31 (td,J=9.59, 2.52 Hz, 1 H), 7.19 (td,J=8.33, 6.72 Hz, 1 H), 7.10 - 7.16 (m, 1 H), 6.53 (s, 1 H), 3.34-3.36 (m, 2 H), 2.86 (dt,J=4.85, 2.24 Hz, 2 H), 2.58 (s, 3 H); MH + 389

[0607]

[0608] Step 2: 2-(2,4-difluorophenyl)-N-methyl-1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (93)

[0609] 2-(2,4-Difluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (240 mg, 1 eq, 0.62 mmol) was dissolved in DCM (15.4 mL, 0.04 M), titanium(IV) isopropoxide (560.5 μL, 3 eq, 1.85 mmol) and 2 M methylamine in THF (6.2 mL, 5 eq, 3.1 mmol) were added, and the mixture was stirred at room temperature for 2 h. After concentrating the reaction solution, MeOH (6.2 mL, 0.1 M) was added, and sodium borohydride (70.1 mg, 3 eq, 1.85 mmol) was slowly added at 0°C and stirred for 5 min. After the reaction was completed, saturated aqueous NaHCO3 solution was added to terminate the reaction, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by normal phase silica gel column chromatography (5-15% MeOH / MC) to obtain 2-(2,4-difluorophenyl)-N-methyl-1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (brown sticky solid, 191 mg, yield 77%).

[0610] 1 H NMR (500 MHz, DMSO-d6) δ 8.40 (d,J=2.45 Hz, 1 H), 7.74 (dd,J=8.41, 2.60 Hz, 1 H), 7.47 (d,J=8.41 Hz, 1 H), 7.30 (td,J=9.63, 2.45 Hz, 1 H), 7.20 (td,J=8.41, 6.72 Hz, 1 H), 7.09 - 7.15 (m, 1 H), 6.37 (s, 1 H), 4.01 - 4.08 (m, 1 H), 3.04 - 3.14 (m, 1 H), 2.90 - 2.99 (m, 1) H), 2.61 - 2.68 (m, 1 H), 2.56 (s, 3H), 2.32 (s, 3 H), 2.11 - 2.21 (m, 1 H); MS m / z 373 (MH +- NH2Me)

[0611]

[0612] [Example 35] 2-(2,4-difluorophenyl)-1-((3,4-dimethylphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (96)

[0613]

[0614]

[0615] Step 1: 2-(2,4-difluorophenyl)-1-((3,4-dimethylphenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (95)

[0616] 2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (150 mg) was added to a solution of 60% sodium hydride dispersion (38.6 mg, 1.5 eq) in THF (3.22 mL) at 0°C, and the mixture was stirred at room temperature for 1 hour. 3,4-dimethylbenzenesulfonyl chloride (145 mg, 1.1 eq) was added to the reaction solution at 0°C, and the mixture was stirred at room temperature for 16 hours. After quenching the reaction with H2O, the mixture was diluted with ethyl acetate, and washed several times with distilled water and brine. 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 2-(2,4-difluorophenyl)-1-((3,4-dimethylphenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (brown oil, 241 mg, yield 83%).

[0617] 1H NMR (500 MHz, DMSO-d6) δ 7.33 - 7.38 (m, 1 H), 7.26 - 7.33 (m, 2 H), 7.10 - 7.18 (m, 3 H), 6.46 (s, 1 H), 3.32 (br dd,J=4.97, 2.22 Hz, 2 H), 2.84 (dt,J=4.78, 2.27 Hz, 2 H), 2.30 (s, 3 H), 2.22 (s, 3 H); MH + 402

[0618]

[0619] Step 2: 2-(2,4-difluorophenyl)-1-((3,4-dimethylphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (96)

[0620] 2-(2,4-Difluorophenyl)-1-((3,4-dimethylphenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (209 mg), titanium isopropoxide (0.47 mL, 3.0 eq), and 2 M methylamine in THF (1.30 mL, 5.0 eq) were added to CH2Cl2 (8.68 mL) and stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure. The concentrated reaction product was dissolved in methanol (8.68 mL), and the resulting solution was cooled to 0°C, NaBH4 (39 mg, 2.0 eq) was added, and the mixture was stirred at room temperature for 40 min. The reaction solution 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 silica gel column chromatography to obtain 2-(2,4-difluorophenyl)-1-((3,4-dimethylphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (brown oil, 123 mg, yield 57%).

[0621] 1H NMR (500 MHz, DMSO-d6) δ 8.84 - 9.03 (m, 1 H), 7.28 - 7.37 (m, 2 H), 7.24 (dd,J=8.02, 2.06 Hz, 1 H), 7.09 - 7.19 (m, 3 H), 6.44 (s, 1 H), 4.41 (br d,J=7.49 Hz, 1 H), 3.15 - 3.26 (m, 1 H), 3.03 (ddd,J=16.54, 9.13, 3.52 Hz, 1 H), 2.78 (dtd,J=14.19, 8.64, 5.81 Hz, 1 H), 2.50 (s, 3 H), 2.37 - 2.45 (m, 1 H), 2.29 (s, 3 H), 2.23 (s, 3 H); MS m / z 386 (MH + - NH2Me)

[0622]

[0623] [Example 36] 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (99)

[0624]

[0625]

[0626] Step 1: 1-((3-fluorophenyl)sulfonyl)-2-phenyl-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (98)

[0627] 2-Phenyl-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (106 mg, 1 eq, 0.54 mmol) was dissolved in DMF (1.8 mL, 0.3 M) and stirred for 5 minutes under nitrogen at 0°C. A 60% sodium hydride dispersion in mineral oil (86 mg, 4 eq, 2.15 mmol) was added and stirred for 1 hour. 3-Fluorobenzenesulfonyl chloride (214 μL, 3 eq, 1.61 mmol) was added and stirred at room temperature for 10 minutes. After completion of the reaction, NaHCO3(aq) was added at 0°C to terminate the reaction and the mixture was extracted twice with ethyl acetate. Sodium sulfate was added to the organic layer, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by normal silica gel column chromatography (30%-50% EA / Hex) to obtain 1-((3-fluorophenyl)sulfonyl)-2-phenyl-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (brown solid 155 mg, yield 81%).

[0628] 1 H NMR (500 MHz, DMSO-d6) δ 7.60 - 7.65 (m, 1 H), 7.55 - 7.60 (m, 1 H), 7.42 - 7.47 (m, 1 H), 7.30 - 7.36 (m, 3 H), 7.14 - 7.18 (m, 1 H), 7.09 - 7.13 (m, 2 H), 6.38 (s, 1 H), 3.36 - 3.39 (m, 2 H), 2.85 (dt,J=5.01, 2.36 Hz, 2 H); MH + 356.

[0629]

[0630] Step 2: 1-((3-Fluorophenyl)sulfonyl)-N-methyl-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (99)

[0631] 1-((3-Fluorophenyl)sulfonyl)-2-phenyl-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (110 mg, 1 eq, 0.31 mmol) was dissolved in MeOH (7.8 mL, 0.04 M), titanium(IV) isopropoxide (468 μL, 5 eq, 1.55 mmol) and 2 M methylamine in THF (1.5 mL, 10 eq, 3.1 mmol) were added, and the mixture was stirred at room temperature for 4 h. Sodium borohydride (117.3 mg, 10 eq, 3.1 mmol) was slowly added, and the mixture was stirred for 1 h. After completion of the reaction, saturated aqueous NaHCO3 solution was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography (2-5% MeOH / EA) to obtain 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (brown gel 74 mg, yield 65%).

[0632] 1 H NMR (500 MHz, DMSO-d6) δ 7.54 - 7.62 (m, 2 H), 7.33 - 7.41 (m, 3 H), 7.22 - 7.26 (m, 1 H), 7.18 - 7.25 (m, 2 H), 7.00 - 7.04 (m, 1 H), 6.23 (s, 1 H), 3.86 (dt,J=4.87, 2.72 Hz, 1 H), 3.01 - 3.10 (m, 1 H), 2.87 - 2.95 (m, 1 H), 2.54 - 2.66 (m, 1 H), 2.20 (s, 3 H), 2.01 - 2.10 (m, 1 H); MS m / z 340 (MH + - NH2Me)

[0633]

[0634] [Example 37] 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (100)

[0635]

[0636]

[0637] 1-((3-Fluorophenyl)sulfonyl)-N-methyl-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (74 mg, 1 eq, 0.20 mmol) was dissolved in ethyl acetate (1 mL, 0.2 M) and stirred at 0°C for 2 min. 1 N HCl in EA (240 μL, 1.2 eq) was added, and the reaction temperature was slowly raised to room temperature. After stirring for 30 min, the mixture was filtered to obtain 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (brown solid, 54 mg, yield 67%).

[0638] 1 H NMR (500 MHz, DMSO-d6) δ 8.63 - 8.92 (br s, 1 H), 7.55 - 7.66 (m, 2 H), 7.40 - 7.47 (m, 1 H), 7.32 - 7.39 (m, 2 H), 7.27 (dt,J=7.30, 1.79 Hz, 1 H), 7.14 (d,J=7.45 Hz, 2 H), 7.07 (dt,J=7.88, 1.79 Hz, 1 H), 6.39 (s, 1 H), 4.43 (br d,J=7.45 Hz, 1 H), 3.18 - 3.27 (m, 1 H), 3.05 - 3.13 (m, 1 H), 2.79 (dtd,J=14.18, 8.66, 5.73 Hz, 1 H), 2.52 (s, 3 H), 2.38 - 2.44 (m, 1 H); MS m / z 371 (MH + - HCl)

[0639]

[0640] [Example 38] N-Methyl-2-phenyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (102)

[0641]

[0642]

[0643] Step 1: 2-Phenyl-1-(pyridin-3-ylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (101)

[0644] 2-Phenyl-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (130 mg, 1 eq, 0.66 mmol) was dissolved in DMF (2.2 mL, 0.3 M) and stirred for 5 minutes under nitrogen at 0°C. A 60% sodium hydride dispersion in mineral oil (63 mg, 4 eq, 2.64 mmol) was added and stirred for 1 hour. Pyridine-3-sulfonyl chloride (234 μL, 3 eq, 1.98 mmol) was added and stirred at room temperature for 1 hour. After completion of the reaction, NaHCO3(aq) was added at 0°C to terminate the reaction and extracted twice with ethyl acetate. Sodium sulfate was added to the organic layer, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by normal silica gel column chromatography (10% MeOH / MC) to obtain 2-phenyl-1-(pyridin-3-ylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (yellow solid, 79 mg, yield 35%).

[0645] 1H NMR (500 MHz, DMSO-d6) δ 8.85 - 8.89 (m, 1 H), 8.47 (d,J=2.29 Hz, 1 H), 7.83 - 7.89 (m, 1 H), 7.52 - 7.61 (m, 1 H), 7.41 - 7.47 (m, 1 H), 7.32 - 7.37 (m, 2 H), 7.06 - 7.13 (m, 2 H), 6.40 (s, 1 H), 3.37 - 3.41 (m, 2 H), 2.84 - 2.87 (m, 2 H); MH + 339

[0646]

[0647] Step 2: N-Methyl-2-phenyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (102)

[0648] 2-Phenyl-1-(pyridin-3-ylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (79 mg, 1 eq, 0.23 mmol) was dissolved in MeOH (5.8 mL, 0.04 M). Titanium(IV) isopropoxide (352 μL, 5 eq, 1.17 mmol) and 2 M methylamine in THF (1.2 mL, 10 eq, 2.33 mmol) were added, and the mixture was stirred at room temperature for 4 h. Sodium borohydride (88.5 mg, 10 eq, 2.33 mmol) was slowly added, and the mixture was stirred for 1 h. After completion of the reaction, saturated aqueous NaHCO3 solution was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by amino silica gel column chromatography (10% MeOH / MC) to obtain N-methyl-2-phenyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (32 mg of yellow sticky solid, yield 39%).

[0649] 1H NMR (500 MHz, DMSO-d6) δ 8.83 (dd,J=4.87, 1.43 Hz, 1 H), 8.41 (d,J=2.29 Hz, 1 H), 7.71 - 7.78 (m, 1 H), 7.54 - 7.60 (m, 1 H), 7.33 - 7.41 (m, 3 H), 7.17 - 7.23 (m, 2 H), 6.25 (s, 1 H), 3.84 - 3.89 (m, 1 H), 3.04 - 3.12 (m, 1 H), 2.93 (ddd,J=16.32, 8.88, 5.15 Hz, 1 H), 2.54 - 2.60 (m, 1 H), 2.20 (s, 3 H), 2.02 - 2.10 (m, 1 H); MS m / z 323 (MH + - NH2Me)

[0650]

[0651] [Example 39] N-Methyl-2-phenyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride (103)

[0652]

[0653]

[0654] N-Methyl-2-phenyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (30 mg, 1 eq, 0.08 mmol) was dissolved in ethyl acetate (1 mL, 0.08 M) and stirred at 0°C for 2 min. 1 M HCl in EA (190 μL, 2.5 eq) was added, and the reaction temperature was slowly raised to room temperature. After stirring for 30 min, the mixture was filtered. The filtered solid was dissolved in methanol and concentrated to give N-methyl-2-phenyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride (32 mg of dark yellow solid, yield 93%).

[0655] 1H NMR (500 MHz, DMSO-d6) δ 9.02 (br s, 2 H), 8.85 (dd,J=4.87, 1.43 Hz, 1 H), 8.44 (d,J=2.29 Hz, 1 H), 7.80 (dt,J=8.02, 2.00 Hz, 1 H), 7.56 (dd,J=8.31, 4.87 Hz, 1 H), 7.40 - 7.47 (m, 1 H), 7.32 - 7.39 (m, 2 H), 7.13 (d,J=6.87 Hz, 2 H), 6.41 (s, 1 H), 4.45 (br dd,J=5.16, 1.72 Hz, 1 H), 3.20 - 3.32 (m, 1 H), 3.06 - 3.16 (m, 1 H), 2.73 - 2.88 (m, 1 H), 2.53 (t,J=5.44 Hz, 3 H), 2.40 - 2.48 (m, 1 H); MS m / z 323 (MH + - NH2Me-2HCl)

[0656]

[0657] [Example 40] N-Methyl-1-((1-methyl-1H-indol-4-yl)sulfonyl)-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (106)

[0658]

[0659]

[0660] Step 1: 1-((1-methyl-1H-indol-4-yl)sulfonyl)-2-phenyl-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (104)

[0661] 2-Phenyl-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (50 mg, 1 eq, 0.25 mmol) was dissolved in DMF (1 mL, 0.3 M) and stirred for 5 minutes under nitrogen at 0°C. A 60% sodium hydride dispersion in mineral oil (40 mg, 4 eq, 1.01 mmol) was added and stirred for 1 hour. 1-Methyl-1H-indole-4-sulfonyl chloride (116 mg, 3 eq, 0.76 mmol) was added and stirred at room temperature for 10 minutes. After completion of the reaction, NaHCO3(aq) was added at 0°C to terminate the reaction and extracted twice with ethyl acetate. Sodium sulfate was added to the organic layer, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by amino silica gel column chromatography (50-100% EA / Hex) to obtain 1-((1-methyl-1H-indol-4-yl)sulfonyl)-2-phenyl-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (18 mg of orange solid, yield 18%).

[0662] 1 H NMR (500 MHz, DMSO-d6) δ 7.83 (d,J=8.02 Hz, 1 H), 7.57 (d,J=3.44 Hz, 1 H), 7.30 - 7.38 (m, 1 H), 7.17 - 7.23 (m, 2 H), 7.00 - 7.05 (m, 1 H), 6.90 - 6.97 (m, 3 H), 6.28 (d,J=4.01 Hz, 1 H), 6.24 (s, 1 H), 3.85 (s, 2 H), 3.48 (s, 3 H), 3.29 - 3.33 (m, 2 H), 2.84 - 2.90 (m, 3) H); MH + 391

[0663]

[0664] Step 2: N-Methyl-1-((1-methyl-1H-indol-4-yl)sulfonyl)-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (105)

[0665] 1-((1-Methyl-1H-indol-4-yl)sulfonyl)-2-phenyl-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (18 mg, 1 eq, 0.04 mmol) was dissolved in MeOH (1.1 mL, 0.04 M), titanium(IV) isopropoxide (67 μL, 5 eq, 0.22 mmol) and 2 M methylamine in THF (222 μL, 10 eq, 0.44 mmol) were added, and the mixture was stirred at room temperature for 4 h. Sodium borohydride (17 mg, 10 eq, 0.44 mmol) was slowly added, and the mixture was stirred for 30 min. After completion of the reaction, saturated aqueous NaHCO3 solution was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by amino silica gel column chromatography (0-10% MeOH / MC) to obtain N-methyl-1-((1-methyl-1H-indol-4-yl)sulfonyl)-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow gel 10 mg, yield 56%).

[0666] 1 H NMR (500 MHz, DMSO-d6) δ 7.78 (br d,J=8.02 Hz, 1 H), 7.51 (d,J=3.44 Hz, 1 H), 7.20 - 7.27 (m, 4 H), 7.03 - 7.11 (m, 3 H), 6.96 (d,J=7.45 Hz, 1 H), 6.28 (s, 1 H), 3.82 (s, 3 H), 3.79 - 3.81 (m, 1 H), 3.23 - 3.27 (m, 1 H), 3.08 - 3.17 (m, 1 H), 2.65 - 2.73 (m, 1 H), 2.54 (s, 3 H), 2.29 - 2.32 (m, 1 H); MS m / z 375 (MH + - NH2Me)

[0667]

[0668] Step 3: N-Methyl-1-((1-methyl-1H-indol-4-yl)sulfonyl)-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (106)

[0669] N-Methyl-1-((1-methyl-1H-indol-4-yl)sulfonyl)-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (10 mg, 1 eq, 0.03 mmol) was dissolved in ethyl acetate (0.5 mL, 0.06 M) and stirred at 0°C for 2 min. 1 M HCl in EA (30 μL, 1.2 eq) was added, and the reaction temperature was slowly raised to room temperature. After stirring for 30 min, the mixture was filtered. The filtered solid was dissolved in methanol and concentrated to give N-methyl-1-((1-methyl-1H-indol-4-yl)sulfonyl)-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (brown solid, 8 mg, yield 74%).

[0670] 1 H NMR (500 MHz, DMSO-d6) δ 8.75 (br s, 2 H), 7.81 (d,J=8.02 Hz, 1 H), 7.53 (d,J=3.44 Hz, 1 H), 7.31 - 7.39 (m, 1 H), 7.21 - 7.27 (m, 2 H), 7.03 - 7.08 (m, 1 H), 6.98 - 7.02 (m, 2 H), 6.95 - 6.98 (m, 1 H), 6.27 (d,J=2.29 Hz, 1 H), 6.24 (s, 1 H), 4.41 - 4.48 (m, 1 H), 3.84 (s, 3 H), 3.22 - 3.27 (m, 1 H), 3.06 - 3.15 (m, 1 H), 2.76 - 2.86 (m, 1 H), 2.53 (t,J=5.44 Hz, 3 H), 2.38 - 2.44 (m, 1 H); MS m / z 375 (MH + - NH2Me - HCl)

[0671]

[0672] [Example 41] 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-(pyridin-3-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride (116)

[0673]

[0674]

[0675] Step 1: tert-Butyl 2-bromo-1H-pyrrole-1-carboxylate (10)

[0676] Pyrrole (5 g, 1 eq, 74.5 mmol) was dissolved in THF (200 mL, 0.4 M) and cooled to -78°C. NBS (13.2 g, 1 eq, 74.5 mmol) was added portionwise and stirred at -20°C for 2 h. After completion of the reaction, the temperature was cooled to -78°C, filtered, and the filtrate was concentrated under reduced pressure. THF (200 mL, 0.4 M) was added to the concentrated residue and nitrogen was added. At room temperature, trimethylamine (20.8 mL, 2 eq, 149.1 mmol), DMAP (182 mg, 0.02 eq, 1.49 mmol), and Boc2O (25.7 mL, 1.5 eq, 111.8 mmol) were added and stirred at room temperature for 8 h. After completion of the reaction, the solvent was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with water. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 2-bromo-1H-pyrrole-1-carboxylate (dark brown oil, crude).

[0677]

[0678] Step 2: 3-(1H-pyrrol-2-yl)pyridine (108)

[0679] tert-Butyl 2-bromo-1H-pyrrole-1-carboxylate (2.8 g, 1 eq, 11.2 mmol) was dissolved in toluene / water / EtOH (37 mL / 6.2 mL / 6.2 mL), and a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (182.6 mg, 0.1 eq, 0.22 mmol), potassium carbonate (3.1 g, 2 eq, 22.4 mmol), and pyridin-3-ylboronic acid (1.5 g, 1.1 eq, 12.3 mmol) were added, and the mixture was stirred at 110°C for 12 h. The reaction mixture was cooled to room temperature and then filtered through a celite ® The mixture was filtered and the filtrate was concentrated under reduced pressure. The concentrated residue was dissolved in MeOH (37 mL, 0.3 M), added to sodium methoxide in MeOH (2 mL), and stirred at room temperature for 20 hours. After the reaction was completed, water was added to quench the reaction. The mixture was extracted twice with ethyl acetate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by amino silica gel column chromatography (2% MeOH / MC) to obtain 3-(1H-pyrrol-2-yl)pyridine (yellow solid 1.23 g, yield 77%).

[0680] 1 H NMR (500 MHz, DMSO-d6) δ 11.45 (br s, 1 H), 8.87 (d,J=2.29 Hz, 1 H), 8.25 - 8.37 (m, 1 H), 7.96 (dt,J=8.02, 2.00 Hz, 1 H), 7.35 (dd,J=8.02, 4.58 Hz, 1 H), 6.93 (td,J=2.58, 1.15 Hz, 1 H), 6.55 - 6.68 (m, 1 H), 6.15 (dt,J=3.44, 2.29 Hz, 1 H); MH + 145.

[0681]

[0682] Step 3: 5-(Pyridin-3-yl)-1H-pyrrole-2-carbaldehyde (109)

[0683] 3-(1H-pyrrol-2-yl)pyridine (878 mg, 1 eq, 6.1 mmol) was added to DMF (1.5 mL, 1.5 eq, 9.1 mmol) and stirred at 0°C. Phosphorus(V) oxychloride (854 μL, 1.5 eq, 9.1 mmol) was added dropwise and stirred at 40°C for 1 h. After completion of the reaction, a KOH aqueous solution of potassium hydroxide (512 mg, 3 eq, 18.3 mmol) dissolved in 20 mL of water was added and heated and stirred at 110°C. After 2 h, the mixture was sufficiently alkalized (pH 8) with sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 5-(pyridin-3-yl)-1H-pyrrole-2-carbaldehyde was obtained by purification by normal silica gel column chromatography (50-100% EA / Hex) (ivory solid 858 mg, yield 82%).

[0684] 1 H NMR (500 MHz, DMSO-d6) δ 9.54 (s, 1 H), 9.10 (d,J=2.29 Hz, 1 H), 8.50 (dd,J=4.58, 1.72 Hz, 1 H), 8.27 (dt,J=8.02, 2.00 Hz, 1 H), 7.45 (dd,J=8.02, 4.01 Hz, 1 H), 7.12 (d,J=4.01 Hz, 1 H), 6.91 (d,J=3.44 Hz, 1 H); MH + 173

[0685]

[0686] Step 4: Ethyl (E)-3-(5-(pyridin-3-yl)-1H-pyrrol-2-yl)acrylate (110)

[0687] 1,4-Dioxane / H2O (2.1 mL / 21 μL) was added to cesium carbonate (2.1 g, 1.5 eq, 6.3 mmol), and triethyl phosphonoacetate (1.7 mL, 2 eq, 8.4 mmol) was added, followed by stirring for 30 minutes. 5-(Pyridin-3-yl)-1H-pyrrole-2-carbaldehyde (720 mg, 1 eq, 4.2 mmol) was dissolved in 1,4-dioxane / H2O (2.1 mL / 21 μL), added, and stirred at 80°C for 6 hours. After the reaction was completed, water was added to quench the reaction. The mixture was extracted twice with ethyl acetate, and 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 (50% EA / Hex) to obtain ethyl (E)-3-(5-(pyridin-3-yl)-1H-pyrrol-2-yl)acrylate (yellow solid, 921 mg, yield 91%).

[0688] 1 H NMR (500 MHz, DMSO-d6) δ 11.73 (br s, 1 H), 8.99 (d,J=2.29 Hz, 1 H), 8.44 (dd,J=4.87, 1.43 Hz, 1 H), 8.11 (dt,J=8.31, 1.86 Hz, 1 H), 7.47 (d,J=15.47 Hz, 1 H), 7.43 (dd,J=7.73, 4.87 Hz, 1 H), 6.79 (dd,J=3.44, 2.29 Hz, 1 H), 6.69 - 6.74 (m, 1 H), 6.45 (d,J=15.47 Hz, 1 H), 4.16 (q,J=7.06 Hz, 2 H), 1.25 (t,J=7.16 Hz, 3 H); MH + 243

[0689]

[0690] Step 5: Ethyl 3-(5-(pyridin-3-yl)-1H-pyrrol-2-yl)propanoate (111)

[0691] Ethyl (E)-3-(5-(pyridin-3-yl)-1H-pyrrol-2-yl)acrylate (921 mg, 1 eq, 3.8 mmol) was dissolved in DCM (12.7 mL, 0.3 M), 5% palladium on carbon (323.6 mg, 0.04 eq, 0.15 mmol) was added, and the mixture was stirred under hydrogen conditions for 18 h. After completion of the reaction, Celite ® The residue was filtered and concentrated under reduced pressure to obtain ethyl 3-(5-(pyridin-3-yl)-1H-pyrrol-2-yl)propanoate (yellow gel 901 mg, yield 97%).

[0692] 1 H NMR (500 MHz, DMSO-d6) δ 11.13 (br s, 1 H), 8.81 (d,J=2.29 Hz, 1 H), 8.29 (dd,J=4.58, 1.15 Hz, 1 H), 7.90 (dt,J=8.02, 2.00 Hz, 1 H), 7.32 (dd,J=8.02, 4.58 Hz, 1 H), 6.50 (t,J=2.86 Hz, 1 H), 5.87 (t,J=2.86 Hz, 1 H), 4.07 (q,J=7.45 Hz, 2 H), 2.82 - 2.90 (m, 2 H), 2.61 - 2.72 (m, 2 H), 1.18 (t,J=7.16 Hz, 3 H); MH + 245

[0693]

[0694] Step 6: 3-(5-(pyridin-3-yl)-1H-pyrrol-2-yl)propanoic acid (112)

[0695] Ethyl 3-(5-(pyridin-3-yl)-1H-pyrrol-2-yl)propanoate (901 mg, 1 eq, 3.7 mmol) was dissolved in THF / H2O (12.6 mL / 3 mL), potassium hydroxide (413.9 mg, 2 eq, 7.37 mmol) was added, and the mixture was stirred at 80°C for 4 hours. After completion of the reaction, 8 mL of 1 N HCl solution was added, and the pH was confirmed to be 7.5. The insoluble solid was filtered to obtain 3-(5-(pyridin-3-yl)-1H-pyrrol-2-yl)propanoic acid (gray solid 553 mg, yield 68%).

[0696] 1 H NMR (500 MHz, DMSO-d6) δ 11.82 - 12.45 (br s, 1 H), 11.15 (br s, 1 H), 8.81 (d,J=2.29 Hz, 1 H), 8.29 (dd,J=4.58, 1.72 Hz, 1 H), 7.90 (dt,J=8.02, 2.00 Hz, 1 H), 7.32 (dd,J=8.02, 5.73 Hz, 1 H), 6.50 (t,J=3.15 Hz, 1 H), 5.85 - 5.91 (m, 1 H), 2.82 (t,J=7.73 Hz, 2 H), 2.57 (t,J=7.73 Hz, 2 H); MH + 217

[0697]

[0698] Step 7: 2-(Pyridin-3-yl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (113)

[0699] Polyphosphoric acid (2.4 g, 3 eq, 7.29 mmol) was placed in a round flask and stirred at 100°C for 30 minutes. 3-(5-(pyridin-3-yl)-1H-pyrrol-2-yl)propanoic acid (523 mg, 1 eq, 2.43 mmol) was added and stirred for 1 hour. After completion of the reaction, water was added at room temperature to quench the reaction and extracted three times with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by normal phase silica gel column chromatography (5-10% MeOH / MC) to obtain 2-(pyridin-3-yl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (yellow solid, 247 mg, yield 51%).

[0700] 1 H NMR (500 MHz, DMSO-d6) δ 12.20 (br s, 1 H), 8.93 (d,J=2.29 Hz, 1 H), 8.44 (dd,J=4.87, 1.43 Hz, 1 H), 8.04 (dt,J=8.31, 1.86 Hz, 1 H), 7.42 (dd,J=8.02, 4.58 Hz, 1 H), 6.75 (s, 1 H), 2.94 - 3.05 (m, 2 H), 2.74 - 2.86 (m, 2 H); MH + 199

[0701]

[0702] Step 8: 1-((3-fluorophenyl)sulfonyl)-2-(pyridin-3-yl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (114)

[0703] 2-(Pyridin-3-yl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (264 mg, 1 eq, 1.34 mmol) was dissolved in DMF (4.1 mL, 0.3 M), and a 60% sodium hydride dispersion in mineral oil (128.5 mg, 4 eq, 5.35 mmol) was added and stirred at room temperature for 1 h. 3-Fluorobenzenesulfonyl chloride (521 μL, 3 eq, 4.02 mmol) was added and stirred for 2 h. After completion of the reaction, water was added to quench the reaction, extraction was performed with ethyl acetate, and 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 (50-100% EA / Hex) to obtain 1-((3-fluorophenyl)sulfonyl)-2-(pyridin-3-yl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (417 mg of brown solid, yield 92%).

[0704] 1 H NMR (500 MHz, DMSO-d6) δ 8.62 (dd,J=4.58, 1.72 Hz, 1 H), 8.24 (d,J=1.72 Hz, 1 H), 7.58 - 7.69 (m, 3 H), 7.42 (dd,J=8.02, 5.16 Hz, 1 H), 7.29 - 7.33 (m, 1 H), 7.26 (dt,J=8.02, 2.00 Hz, 1 H), 6.55 (s, 1 H), 3.35 - 3.39 (m, 2 H), 2.85 - 2.89 (m, 2 H); MH + 357

[0705]

[0706] Step 9: 1-((3-Fluorophenyl)sulfonyl)-N-methyl-2-(pyridin-3-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (115)

[0707] 1-((3-Fluorophenyl)sulfonyl)-2-(pyridin-3-yl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (120 mg, 1 eq, 0.34 mmol) was dissolved in methanol (8.4 mL, 0.04 M), titanium(IV) isopropoxide (509.1 μL, 5 eq, 1.68 mmol) and 2 M methylamine in THF (1.7 mL, 10 eq, 3.34 mmol) were added, and the mixture was stirred at room temperature for 4 h. Sodium borohydride (127.4 mg, 10 eq, 3.34 mmol) was slowly added, and the mixture was stirred for 30 min. After the reaction was completed, saturated aqueous NaHCO3 solution was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography (5-10% MeOH / MC) to obtain 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-(pyridin-3-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow gel 14 mg, yield 11%).

[0708] 1 H NMR (500 MHz, DMSO-d6) δ 8.57 (dd,J=4.87, 1.43 Hz, 1 H), 8.35 (d,J=2.29 Hz, 1 H), 7.67 (dt,J=7.88, 1.79 Hz, 1 H), 7.56 - 7.64 (m, 2 H), 7.41 (dd,J=8.02, 4.58 Hz, 1 H), 7.19 - 7.25 (m, 1 H), 7.06 - 7.11 (m, 1 H), 6.38 - 6.40 (m, 1 H), 3.86 - 3.92 (m, 1 H), 3.02 - 3.12 (m, 1 H), 2.92 (ddd,J=16.32, 8.88, 5.16 Hz, 1 H), 2.55 - 2.60 (m, 1 H), 2.22 (s, 3 H), 2.04 - 2.11 (m, 1 H); MH + 372

[0709]

[0710] Step 10: 1-((3-Fluorophenyl)sulfonyl)-N-methyl-2-(pyridin-3-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride (116)

[0711] 1-((3-Fluorophenyl)sulfonyl)-N-methyl-2-(pyridin-3-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (14 mg, 1 eq, 0.04 mmol) was dissolved in ethyl acetate (0.5 mL, 0.1 M) and stirred at 0°C for 10 min. 1 M HCl in EA (90 μL, 2.4 eq) was added, and the reaction temperature was slowly raised to room temperature. After stirring for 30 min, the mixture was filtered. The filtered solid was dissolved in methanol and concentrated to give 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-(pyridin-3-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride (brown solid, 13 mg, yield 79%).

[0712] 1 H NMR (500 MHz, DMSO-d6) δ 9.11 (br s, 2 H), 8.66 (dd,J=4.87, 1.43 Hz, 1 H), 8.38 (d,J=1.72 Hz, 1 H), 7.76 (br d,J=7.45 Hz, 1 H), 7.60 - 7.66 (m, 2 H), 7.54 (dd,J=7.45, 5.16 Hz, 1 H), 7.25 - 7.30 (m, 1 H), 7.17 - 7.22 (m, 1 H), 6.58 (s, 1 H), 4.47 (br dd,J=4.87, 2.00 Hz, 1 H), 3.25 (ddd,J=14.75, 8.45, 6.59 Hz, 1 H), 3.05 - 3.14 (m, 1 H), 2.76 - 2.87 (m, 1 H), 2.53 (t,J=5.44 Hz, 3 H), 2.42 - 2.48 (m, 1 H); MS m / z 372 (MH + - 2HCl)

[0713]

[0714] [Example 42] 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-(o-tolyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (125)

[0715]

[0716]

[0717] Step 1: 2-(o-tolyl)-1H-pyrrole (118)

[0718] Tert-Butyl 2-bromo-1H-pyrrole-1-carboxylate (7.3 g) was dissolved in a mixed solvent of toluene (81 mL), H2O (10 mL), and ethanol (10 mL), and o-tolylboronic acid (4.1 g), a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1.7 g), and potassium carbonate (8.4 g) were added, and stirred at 110°C for 16 h. The reaction solution was cooled to 20-25°C and then filtered through a celite ® It was filtered under reduced pressure and washed with EA. The filtrate was concentrated under reduced pressure, diluted with EA, and washed 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, diluted with MeOH (100 mL), 33% sodium methoxide in MeOH (30 mL) was added, and stirred at room temperature for 16 hours. The reactant was concentrated under reduced pressure, diluted with EA, and washed with distilled water and brine. The extracted organic layer was dried over Na2SO4, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain 2-(o-tolyl)-1H-pyrrole. The synthesized compound was used in the next reaction without a separate purification process (black solid, crude).

[0719] 1H NMR (500 MHz, DMSO-d6) δ 10.96 (br s, 1 H), 7.34 (dd,J=7.64, 1.38 Hz, 1 H), 7.14 - 7.23 (m, 2 H), 7.06 - 7.13 (m, 1 H), 6.80 (td,J=2.67, 1.53 Hz, 1 H), 6.19 (ddd,J=3.55, 2.41, 1.53 Hz, 1 H), 6.09 (dt,J=3.36, 2.52 Hz, 1 H), 2.35 (s, 3 H); MH + 158

[0720]

[0721] Step 2: 5-(o-tolyl)-1H-pyrrole-2-carbaldehyde (119)

[0722] 2-(o-Tolyl)-1H-pyrrole (1.3 g) was dissolved in DMF (10 mL), and phosphorus(V) oxychloride (1.19 mL) was slowly added dropwise at 0°C, and the reaction mixture was stirred at 40°C for 30 minutes. 1 N NaOH aqueous solution (40 mL) was slowly added dropwise and stirred at 110°C for 2 hours. The reaction was quenched by adding distilled water, diluted with EA, and washed 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 silica gel column chromatography to obtain 5-(o-tolyl)-1H-pyrrole-2-carbaldehyde (brown solid 1.02 g, yield 73%).

[0723] 1 H NMR (500 MHz, DMSO-d6) δ 12.16 (br s, 1 H), 9.46 (s, 1 H), 7.37 - 7.45 (m, 1 H), 7.17 - 7.31 (m, 3 H), 7.04 (d,J=3.82 Hz, 1 H), 6.40 (d,J=3.82 Hz, 1 H), 2.34 (s, 3 H); MH + 186

[0724]

[0725] Step 3: Ethyl (E)-3-(5-(o-tolyl)-1H-pyrrol-2-yl)acrylate (120)

[0726] Triethyl phosphonoacetate (1.48 mL) and cesium carbonate (3.036 g) were diluted in a mixed solvent of 1,4-dioxane (20 mL) and H2O (2 mL) and stirred at room temperature for 30 minutes. 5-(o-tolyl)-1H-pyrrole-2-carbaldehyde (1.15 g) was added to the reaction mixture and stirred at 80°C for 24 hours. Distilled water was added to quench the reaction, EA was added, the mixture was diluted, and the mixture was washed 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, washed with petroleum ether, and dried to obtain ethyl (E)-3-(5-(o-tolyl)-1H-pyrrol-2-yl)acrylate (yellow solid 950 mg, yield 60%).

[0727] 1 H NMR (500 MHz, DMSO-d6) δ 7.39 - 7.46 (m, 2 H), 7.17 - 7.28 (m, 3 H), 6.66 (dd,J=3.52, 2.45 Hz, 1 H), 6.31 (dd,J=3.59, 2.37 Hz, 1 H), 6.31 (d,J=15.74 Hz, 1 H), 4.10 (q,J=7.03 Hz, 2 H), 2.36 (s, 3 H), 1.20 (t,J=7.11 Hz, 3 H); MH + 256

[0728]

[0729] Step 4: Ethyl 3-(5-(o-tolyl)-1H-pyrrol-2-yl)propanoate (121)

[0730] Ethyl (E)-3-(5-(o-tolyl)-1H-pyrrol-2-yl)acrylate (950 mg) was diluted in DCM (12 mL) and 10% palladium on carbon (100 mg) was added. The reaction mixture was replaced with hydrogen gas and stirred at room temperature for 24 hours. After completion of the reaction, Celite was used. ®The residue was filtered under reduced pressure and washed with EA. The filtrate was concentrated under reduced pressure to obtain ethyl 3-(5-(o-tolyl)-1H-pyrrol-2-yl)propanoate. The synthesized compound was used in the next reaction without any separate purification process (yellow solid, crude).

[0731] 1 H NMR (500 MHz, DMSO-d6) δ 10.70 (br s, 1 H), 7.28 - 7.38 (m, 1 H), 7.13 - 7.21 (m, 2 H), 7.02 - 7.10 (m, 1 H), 6.05 (t,J=2.98 Hz, 1 H), 5.81 (t,J=2.90 Hz, 1 H), 4.03 (q,J=7.03 Hz, 2 H), 2.76 - 2.86 (m, 2 H), 2.57 - 2.65 (m, 2 H), 2.34 (s, 3 H), 1.14 (t,J=7.11 Hz, 3 H); MH + 258.

[0732]

[0733] Step 5: 3-(5-(o-tolyl)-1H-pyrrol-2-yl)propanoic acid (122)

[0734] Ethyl 3-(5-(o-tolyl)-1H-pyrrol-2-yl)propanoate (957 mg) was dissolved in a mixed solvent of THF (13 mL) and H2O (3 mL), potassium hydroxide (417 mg) was added, and the mixture was stirred at 80°C for 3 hours. Distilled water was added to quench the reaction, and 1 N HCl aqueous solution was slowly added dropwise, diluted with EA, and washed 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 3-(5-(o-tolyl)-1H-pyrrol-2-yl)propanoic acid. The synthesized compound was used in the next reaction without a separate purification process (yellow solid, crude).

[0735] 1H NMR (500 MHz, DMSO-d6) δ 11.54 - 12.69 (m, 1 H), 10.70 (br s, 1 H), 7.34 (d,J=7.18 Hz, 1 H), 7.11 - 7.23 (m, 2 H), 7.01 - 7.10 (m, 1 H), 6.05 (t,J=2.98 Hz, 1 H), 5.81 (t,J=2.75 Hz, 1 H), 2.77 (t,J=7.72 Hz, 2 H), 2.52 (t,J=7.79 Hz, 2 H), 2.35 (s, 3 H); MH + 230

[0736]

[0737] Step 6: 2-(o-tolyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (123)

[0738] Polyphosphoric acid (3.1 g) was stirred at 100°C, and 3-(5-(o-tolyl)-1H-pyrrol-2-yl)propanoic acid (650 mg) was slowly added dropwise. The reaction mixture was stirred at 100°C for 10 minutes. After completion of the reaction, MeOH and EA were added, diluted, and washed 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 Hex was added to precipitate a solid, which was then filtered to obtain 2-(o-tolyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (brown solid 365 mg, yield 56%).

[0739] 1 H NMR (500 MHz, DMSO-d6) δ 11.70 (br s, 1 H), 7.35 (dd,J=7.34, 1.83 Hz, 1 H), 7.23 - 7.27 (m, 1 H), 7.17 - 7.23 (m, 2 H), 6.21 (d,J=0.61 Hz, 1 H), 2.85 - 2.94 (m, 2 H), 2.68 - 2.75 (m, 2 H), 2.35 (s, 3 H); MH + 212

[0740]

[0741] Step 7: 1-((3-fluorophenyl)sulfonyl)-2-(o-tolyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (124)

[0742] 2-(o-Tolyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (200 mg) was dissolved in THF (3 mL), and a 60% sodium hydride dispersion in mineral oil (56 mg) was added at 0°C. The reaction mixture was purged with nitrogen and stirred at room temperature for 1 h. 3-Fluorobenzenesulfonyl chloride (150 μL) was added, and the mixture was stirred at room temperature for 16 h. The reaction was quenched by adding distilled water, and extracted with EA. 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-fluorophenyl)sulfonyl)-2-(o-tolyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (yellow solid, 311 mg, yield 90%).

[0743] 1 H NMR (500 MHz, DMSO-d6) δ 7.60 - 7.66 (m, 1 H), 7.55 - 7.60 (m, 1 H), 7.29 - 7.35 (m, 2 H), 7.05 - 7.18 (m, 3 H), 6.85 (dd,J=7.49, 1.22 Hz, 1 H), 6.32 (s, 1 H), 3.30 - 3.39 (m, 2 H), 2.82 (t,J=4.74 Hz, 2 H), 1.72 (s, 3 H); MH + 370

[0744]

[0745] Step 8: 1-((3-Fluorophenyl)sulfonyl)-N-methyl-2-(o-tolyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (125)

[0746] 1-((3-Fluorophenyl)sulfonyl)-2-(o-tolyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (309 mg) was dissolved in DCM (8 mL) and titanium(IV) isopropoxide (748 μL) and 2 M methylamine (2.1 mL) was added dropwise and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and diluted with MeOH (8 mL). After cooling the reaction mixture to 0°C, sodium borohydride (157 mg) was slowly added dropwise and stirred at room temperature for 1 hour. The reaction mixture was quenched by adding distilled water, diluted with EA, and washed 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 silica gel column chromatography to obtain 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-(o-tolyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow solid 240 mg, yield 75%).

[0747] 1 H NMR (500 MHz, DMSO-d6) δ 7.57 - 7.65 (m, 2 H), 7.33 (td,J=7.53, 1.30 Hz, 1 H), 7.25 - 7.30 (m, 1 H), 7.20 (br d,J=6.11 Hz, 1 H), 7.14 (br s, 1 H), 7.00 (br d,J=7.95 Hz, 1 H), 6.82 - 6.95 (m, 1 H), 6.21 (br s, 1 H), 4.03 - 4.24 (m, 1 H), 3.44 (br d,J=8.25 Hz, 1 H), 3.40 - 3.49 (m, 1 H), 3.10 - 3.23 (m, 1 H), 2.91 - 3.09 (m, 1 H), 2.64 - 2.78 (m, 1 H), 2.37 (s, 3 H), 2.23 (td,J=8.56, 3.36 Hz, 1 H), 1.71 - 1.95 (m, 3 H); MH + 354

[0748]

[0749] [Example 43] 2-(3-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (134)

[0750]

[0751]

[0752] Step 1: tert-Butyl 2-bromo-1H-pyrrole-1-carboxylate (10)

[0753] Pyrrole (2 g, 1 eq, 29.81 mmol) was dissolved in THF (74.5 mL, 0.4 M) and cooled to -78°C. NBS (5.3 g, 1 eq, 29.81 mmol) was added portionwise and stirred at -20°C for 2 h. After completion of the reaction, the temperature was cooled to -78°C, filtered, and the filtrate was concentrated under reduced pressure. THF (74.5 mL, 0.4 M) was added to the concentrated residue and nitrogen was supplied. At room temperature, trimethylamine (8.3 mL, 2 eq, 59.62 mmol), DMAP (72.8 mg, 0.02 eq, 0.60 mmol), and Boc2O (10.2 mL, 1.5 eq, 44.72 mmol) were added and stirred at room temperature for 8 h. After the reaction was completed, the solvent was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with water. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 2-bromo-1H-pyrrole-1-carboxylate (dark brown oil, crude).

[0754]

[0755] Step 2: 2-(3-fluorophenyl)-1H-pyrrole (127)

[0756] tert-Butyl 2-bromo-1H-pyrrole-1-carboxylate (7.2 g, 1 eq, 29.81 mmol) was dissolved in toluene / water / EtOH (99.4 mL / 16.6 mL / 16.6 mL), and a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1.2 mg, 0.1 eq, 1.49 mmol), potassium carbonate (8.2 g, 2 eq, 59.62 mmol), and (3-fluorophenyl)boronic acid (4.6 g, 1.1 eq, 32.79 mmol) were added, and the mixture was stirred at 110°C for 12 h. The reaction mixture was cooled to room temperature and then filtered through a celite ® The mixture was filtered and the filtrate was concentrated under reduced pressure. The concentrated residue was dissolved in MeOH (99.4 mL 0.3 M), added to sodium methoxide in MeOH (15 mL), and stirred at room temperature for 20 hours. After completion of the reaction, water was added to quench the reaction. The mixture was extracted twice with ethyl acetate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by normal phase silica gel column chromatography (10% EA / Hex) to obtain 2-(3-fluorophenyl)-1H-pyrrole (brown solid 4.8 g, yield 100%).

[0757] 1 H NMR (500 MHz, Methanol-d4) δ 7.98 (s, 1 H), 7.45 - 7.47 (m, 1 H), 7.34 - 7.38 (m, 1 H), 7.30 - 7.32 (m, 1 H), 7.25 - 7.29 (m, 1 H), 6.81 (dd,J=2.67, 1.45 Hz, 1 H), 6.51 (dd,J=3.52, 1.53 Hz, 1 H), 6.15 (dd,J=3.52, 2.75 Hz, 1 H); MH + 162

[0758]

[0759] Step 3: 5-(3-fluorophenyl)-1H-pyrrole-2-carbaldehyde (128)

[0760] 2-(3-Fluorophenyl)-1H-pyrrole (4.8 g, 1 eq, 29.8 mmol) was added DMF (7.3 mL, 1.5 eq, 44.72 mmol) and stirred at 0°C. Phosphorus(V) oxychloride (4.2 mL, 1.5 eq, 44.72 mmol) was added dropwise and stirred at 40°C for 1 h. After completion of the reaction, sodium hydroxide (1.8 g, 3 eq, 89.4 mmol) was dissolved in distilled water (186 mL, 0.16 M), NaOH aqueous solution was added, and the mixture was heated and stirred at 110°C. After 2 h, the mixture was sufficiently alkalized with sodium bicarbonate solution to confirm that the pH was approximately 8, and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 5-(3-fluorophenyl)-1H-pyrrole-2-carbaldehyde was obtained by purification by normal silica gel column chromatography (10-50% EA / Hex) (brown solid 3.0 g, yield 53.9%).

[0761] 1 H NMR (500 MHz, DMSO-d6) δ 12.37 - 12.63 (m, 1 H), 9.51 (s, 1 H), 7.80 (dt,J=10.85, 2.06 Hz, 1 H), 7.73 - 7.77 (m, 1 H), 7.46 (td,J=8.02, 6.27 Hz, 1 H), 7.12 - 7.18 (m, 1 H), 7.09 (d,J=3.97 Hz, 1 H), 6.89 (d,J=3.97 Hz, 1 H); MH + 190

[0762]

[0763] Step 4: Ethyl (E)-3-(5-(3-fluorophenyl)-1H-pyrrol-2-yl)acrylate (129)

[0764] Cesium carbonate (7.7 g, 1.5 eq, 23.78 mmol) was added to 1,4-dioxane / H2O (8 mL / 80 μL), followed by triethyl phosphonoacetate (3.8 mL, 1.2 eq, 18.97 mmol), and stirred for 30 minutes. 5-(3-Fluorophenyl)-1H-pyrrole-2-carbaldehyde (3.0 g, 1 eq, 15.86 mmol) was dissolved in 1,4-dioxane / H2O (8 mL / 8 μL), added, and stirred at 80°C for 6 hours. After the reaction was completed, water was added to quench the reaction. The mixture was extracted twice with ethyl acetate, and 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 (50% EA / Hex) to obtain ethyl (E)-3-(5-(3-fluorophenyl)-1H-pyrrol-2-yl)acrylate (yellow solid 3.11 g, yield 74%).

[0765] 1 H NMR (500 MHz, DMSO-d6) δ 11.64 (br s, 1 H), 7.58 - 7.65 (m, 2 H), 7.41 - 7.49 (m, 2 H), 7.04 - 7.09 (m, 1 H), 6.77 (dd,J=3.74, 2.22 Hz, 1 H), 6.69 (dd,J=3.67, 1.99 Hz, 1 H), 6.45 (d,J=15.89 Hz, 1 H), 4.15 (q,J=7.13 Hz, 2 H), 1.20 - 1.30 (m, 3 H); MH + 260

[0766]

[0767] Step 5: Ethyl 3-(5-(3-fluorophenyl)-1H-pyrrol-2-yl)propanoate (130)

[0768] Ethyl (E)-3-(5-(3-fluorophenyl)-1H-pyrrol-2-yl)acrylate (3.1 mg, 1 eq, 11.99 mmol) was dissolved in DCM (40 mL, 0.3 M), 5% palladium on carbon (1.0 g, 0.04 eq, 0.48 mmol) was added, and the mixture was stirred under hydrogen conditions for 18 h. After completion of the reaction, Celite ® The solution was filtered and the filtrate was concentrated under reduced pressure to obtain ethyl 3-(5-(3-fluorophenyl)-1H-pyrrol-2-yl)propanoate (yellow solid 2.9 g, yield 92%).

[0769] 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (br s, 1 H), 7.37 - 7.43 (m, 2 H), 7.31 - 7.36 (m, 1 H), 6.87 - 6.93 (m, 1 H), 6.44 - 6.48 (m, 1 H), 5.84 (dd,J=3.29, 2.52 Hz, 1 H), 4.07 (q,J=7.13 Hz, 2 H), 2.81 - 2.87 (m, 2 H), 2.62 - 2.67 (m, 2 H), 1.18 (t,J=7.11 Hz, 3 H); MH + 262

[0770]

[0771] Step 6: 3-(5-(3-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid (131)

[0772] Ethyl 3-(5-(3-fluorophenyl)-1H-pyrrol-2-yl)propanoate (2.9 g, 1 eq, 11.02 mmol) was dissolved in THF / H2O (36.7 mL / 9.2 mL), and potassium hydroxide (1.2 g, 2 eq, 22.04 mmol) was added. The mixture was stirred at 80°C for 4 hours. After completion of the reaction, 1 N HCl solution (25 mL) was added, and the pH was confirmed to be 3. The mixture was extracted twice with ethyl acetate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 3-(5-(3-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid (yellow solid, 2.5 g, yield 98%).

[0773] 1 H NMR (500 MHz, DMSO-d6) δ 12.15 (br s, 1 H), 11.04 (s, 1 H), 7.37 - 7.43 (m, 2 H), 7.33 (td,J=8.06, 6.34 Hz, 1 H), 6.86 - 6.92 (m, 1 H), 6.44 - 6.48 (m, 1 H), 5.85 (t,J=2.45 Hz, 1 H), 2.81 (t,J=7.72 Hz, 2 H), 2.54 - 2.60 (m, 2 H); MH + 234

[0774]

[0775] Step 7: 2-(3-fluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (132)

[0776] Polyphosphoric acid (8.2 g, 3 eq, 24.44 mmol) was placed in a round flask and stirred at 100°C for 30 minutes. 3-(5-(3-Fluorophenyl)-1H-pyrrol-2-yl)propanoic acid (1.9 g, 1 eq, 8.15 mmol) was added and stirred for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate solution was added at room temperature to sufficiently alkalize the mixture and extracted three times with EA. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and DCM was added to the concentrated residue. The resulting solid was filtered to obtain 2-(3-fluorophenyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (brown solid 1 g, yield 62%).

[0777] 1 H NMR (500 MHz, DMSO-d6) δ 7.51 - 7.61 (m, 2 H), 7.37 - 7.45 (m, 1 H), 6.99 - 7.08 (m, 1 H), 6.68 (s, 1 H), 2.88 - 2.97 (m, 2 H), 2.70 - 2.77 (m, 2 H); MH + 216

[0778]

[0779] Step 8: 2-(3-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (133)

[0780] 2-(3-Fluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (200 mg, 1 eq, 0.93 mmol) was dissolved in THF (3.1 mL, 0.3 M), and a 60% sodium hydride dispersion in mineral oil (55.8 mg, 1.5 eq, 1.39 mmol) was added and stirred at room temperature for 1 h. 3-Fluorobenzenesulfonyl chloride (136.2 μL, 1.1 eq, 1.02 mmol) was added and stirred for 1 h. After completion of the reaction, water was added to quench the reaction, and the organic layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by normal silica gel column chromatography (20-50% EA / Hex) to obtain 2-(3-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (brown solid, 212 mg, yield 57%).

[0781] 1 H NMR (500 MHz, DMSO-d6) δ 7.63 - 7.68 (m, 1 H), 7.58 - 7.63 (m, 1 H), 7.40 (td,J=7.95, 6.11 Hz, 1 H), 7.34 - 7.37 (m, 1 H), 7.29 - 7.33 (m, 1 H), 7.27 (dt,J=8.18, 2.18 Hz, 1 H), 6.97 (dt,J=7.60, 1.24 Hz, 1 H), 6.94 (ddd,J=9.82, 2.48, 1.60 Hz, 1 H), 6.47 (s, 1 H), 3.36 - 3.38 (m, 2 H), 2.86 (dt,J=4.85, 2.24 Hz, 2 H); MH + 374

[0782]

[0783] Step 9: 2-(3-Fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (134)

[0784] 2-(3-Fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (212 mg, 1 eq, 0.57 mmol) was dissolved in DCM (14.2 mL, 0.04 M), titanium(IV) isopropoxide (515.5 μL, 3 eq, 1.71 mmol) and 2 M methylamine in THF (5.7 mL, 5 eq, 2.84 mmol) were added, and the mixture was stirred at room temperature for 4 h. Sodium borohydride (64.5 mg, 3 eq, 1.71 mmol) was slowly added, and the mixture was stirred for 30 min. After completion of the reaction, saturated aqueous NaHCO3 solution was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography (5-20% MeOH / MC) to obtain 2-(3-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (brown gel 141 mg, yield 62%).

[0785] 1 H NMR (500 MHz, DMSO-d6) δ 7.56 - 7.65 (m, 2 H), 7.40 (td,J=7.95, 6.27 Hz, 1 H), 7.21 - 7.29 (m, 2 H), 7.10 (dt,J=8.02, 2.10 Hz, 1 H), 7.00 - 7.06 (m, 2 H), 6.33 (s, 1 H), 3.88 (dt,J=4.47, 2.96 Hz, 1 H), 3.01 - 3.12 (m, 1 H), 2.87 - 2.97 (m, 1 H), 2.53 - 2.61 (m, 1 H), 2.21 (s, 3 H), 2.02 - 2.10 (m, 1 H); MS m / z 358 (MH + - NH2Me)

[0786]

[0787] [Example 44] 2-(2,4-difluorophenyl)-N-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (137)

[0788]

[0789]

[0790] Step 1: 2-(2,4-difluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (136)

[0791] 2-(2,4-Difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (200 mg) was dissolved in THF (2.9 mL), and a 60% sodium hydride dispersion in mineral oil (51 mg) was added. The reaction mixture was purged with nitrogen and stirred at room temperature for 1 hour. 1-Methyl-1H-imidazole-4-sulfonyl chloride (185.8 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by adding distilled water at 0°C, and extracted with EA. 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 2-(2,4-difluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (yellow solid, 104 mg, yield 32%).

[0792] 1H NMR (500 MHz, DMSO-d6) δ 7.87 (d,J=0.92 Hz, 1 H), 7.76 (d,J=1.07 Hz, 1 H), 7.31 (td,J=9.55, 2.60 Hz, 1 H), 7.22 (td,J=8.44, 6.65 Hz, 1 H), 7.07 - 7.14 (m, 1 H), 6.43 (s, 1 H), 3.67 (s, 3 H), 3.25 (dt,J=4.89, 2.29 Hz, 2 H), 2.83 (dt,J=4.89, 2.29 Hz, 2 H); MH + 378

[0793]

[0794] Step 2: 2-(2,4-difluorophenyl)-N-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (137)

[0795] 2-(2,4-difluorophenyl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (104 mg) was dissolved in DCM (2.75 mL) and titanium(IV) isopropoxide (247 μL) and 2 M methylamine (687 μL) was added dropwise and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and diluted with MeOH (2.75 mL). The reaction mixture was cooled to 0°C, sodium borohydride (52 mg) was slowly added dropwise, and stirred at room temperature for 1 hour. The reaction was quenched by adding distilled water, diluted with EA, and washed 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 silica gel column chromatography to obtain 2-(2,4-difluorophenyl)-N-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (yellow solid 35 mg, yield 32%).

[0796] 1H NMR (500 MHz, DMSO-d6) δ 7.79 (d,J=1.07 Hz, 1 H), 7.65 (d,J=1.22 Hz, 1 H), 7.17 - 7.30 (m, 2 H), 7.06 (td,J=8.52, 2.22 Hz, 1 H), 6.19 (s, 1 H), 3.81 - 3.90 (m, 1 H), 3.65 (s, 3 H), 2.95 - 3.04 (m, 1 H), 2.80 - 2.89 (m, 1 H), 2.52 - 2.60 (m, 1 H), 2.25 (s, 3 H), 2.00 - 2.05 (m, 1 H); MS m / z 362 (MH + - NH2Me)

[0797]

[0798] [Example 45] (R)-2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (138) and [Example 46] (S)-2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (139)

[0799]

[0800]

[0801] 2-(2-Fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine was separated using a chiral HPLC column (CHIRALPAK IG-3, 0.03% diethylamine in Hex / EtOH (7 / 3)). t R = 11.876 (> 99% ee) for (R)-2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine, 1H NMR (500 MHz, DMSO-d6) δ 8.87 (dd,J=1.5, 4.9 Hz, 1 H), 8.49 (dd,J=0.8, 2.4 Hz, 1 H), 7.82 - 7.84 (m, 1 H), 7.60 - 7.63 (m, 1 H), 7.47 - 7.51 (m, 1 H), 7.19 - 7.23 (m, 2 H), 7.13 - 7.16 (m, 1 H), 6.32 (s, 1 H), 3.86 - 3.88 (m, 1 H), 3.02 - 3.07 (m, 1 H), 2.90 - 2.93 (m, 1) H), 2.55 - 2.62 (m, 1 H), 2.21 (s, 3 H), 2.04 - 2.08 (m, 1 H); MS m / z 341 (MH + - NH2Me) was obtained, and t R = 18.960 (> 96% ee) at (S)-2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine, 1 H NMR (500 MHz, DMSO-d6) δ 8.87 (dd,J=1.5, 4.9 Hz, 1 H), 8.49 (dd,J=0.8, 2.4 Hz, 1 H), 7.82 - 7.84 (m, 1 H), 7.60 - 7.63 (m, 1 H), 7.47 - 7.51 (m, 1 H), 7.19 - 7.23 (m, 2 H), 7.13 - 7.16 (m, 1 H), 6.32 (s, 1 H), 3.86 - 3.88 (m, 1 H), 3.02 - 3.07 (m, 1 H), 2.90 - 2.93 (m, 1) H), 2.55 - 2.62 (m, 1 H), 2.21 (s, 3 H), 2.04 - 2.08 (m, 1 H); MS m / z 341 (MH + - NH2Me) was obtained.

[0802]

[0803] [Example 47] (R)-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (140) and [Example 48] (S)-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride (141)

[0804]

[0805]

[0806] 2-(2-Fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine was separated using a chiral HPLC column (CHIRALPAK OJ-H, 0.03% diethylamine in Hex / EtOH (7 / 3)). t R = 7.265 (> 98% ee) of (R)-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride, 1 H NMR (400 MHz, DMSO-d6) δ 8.74 - 8.83 (br s, 1 H), 7.64 - 7.66 (m, 2 H), 7.62 - 7.64 (m, 1 H), 7.32 - 7.34 (m, 1 H), 7.16 - 7.22 (m, 3 H), 7.07 - 7.10 (m, 1 H), 6.47 (s, 1 H), 4.45 - 4.47 (m, 1 H), 3.17 - 3.28 (m, 1 H), 3.07 - 3.09 (m, 1 H), 2.80 - 2.83 (m, 1 H), 2.54 (s, 3) H), 2.32 - 2.44 (m, 1 H); MS m / z 358 (MH + - NH2Me) was obtained, and t R= 9.305 (> 95% ee) of (S)-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride, 1 H NMR (400 MHz, DMSO-d6) δ 8.74 - 8.83 (br s, 1 H), 7.64 - 7.66 (m, 2 H), 7.62 - 7.64 (m, 1 H), 7.32 - 7.34 (m, 1 H), 7.16 - 7.22 (m, 3 H), 7.07 - 7.10 (m, 1 H), 6.47 (s, 1 H), 4.45 - 4.47 (m, 1 H), 3.17 - 3.28 (m, 1 H), 3.07 - 3.09 (m, 1 H), 2.80 - 2.83 (m, 1 H), 2.54 (s, 3) H), 2.32 - 2.44 (m, 1 H); MS m / z 358 (MH + - NH2Me) was obtained.

[0807]

[0808] [Example 49] 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-4-amine hydrochloride (149)

[0809]

[0810]

[0811] Step 1: 2-Phenyl-5,6-dihydrocyclopenta[c]pyrrole-4(2H)-one (144)

[0812] 5,6-Dihydrocyclopenta[c]pyrrole-4(2H)-one (500 mg, 1 eq, 4.13 mmol) was dissolved in 1,4-dioxane, and XPhos (393.5 mg, 0.2 eq, 0.83 mmol), tris(dibenzylideneacetone)dipalladium(0) (378.0 mg, 0.1 eq, 0.41 mmol), potassium carbonate (1140 mg, 2 eq, 8.25 mmol), and bromobenzene (475.2 μL, 1.1 eq, 4.54 mmol) were added, followed by stirring at 110°C for 22 hours. After completion of the reaction, water and brine were added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by normal silica gel column chromatography (10-50% EA / Hex) to obtain 2-phenyl-5,6-dihydrocyclopenta[c]pyrrol-4(2H)-one (544 mg of white solid, yield 67%).

[0813] 1 H NMR (500 MHz, DMSO-d6) δ 7.79 (d,J=1.72 Hz, 1 H), 7.66 (d,J=8.02 Hz, 2 H), 7.51 (t,J=7.21 Hz, 2 H), 7.36 (t,J=7.13 Hz, 1 H), 7.28 (d,J=1.15 Hz, 1 H), 2.88 - 2.92 (m, 2 H), 2.73 - 2.81 (m, 2 H); MH + 198

[0814]

[0815] Step 2: 1-((3-fluorophenyl)thio)-2-phenyl-5,6-dihydrocyclopenta[c]pyrrole-4(2H)-one (146)

[0816] 3-Fluorobenzenethiol (1.1 mL, 4 eq, 10.42 mmol) was dissolved in DCM (8.7 mL, 0.3 M), N-chlorosuccinimide (1.6 g, 4.5 eq, 11.73 mmol) was added at 0°C, and the mixture was stirred at 0°C for 15 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was washed with N-hexane and filtered. The filtrate was concentrated under reduced pressure to obtain 3-fluorophenyl hypochlorothioite. 2-Phenyl-5,6-dihydrocyclopenta[c]pyrrol-4(2H)-one (514 mg, 1 eq, 2.61 mmol) was dissolved in DCM (8.7 mL, 0.3 M), 3-fluorophenyl hypochlorothioite was added at 0°C, and the mixture was stirred at room temperature for 24 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted twice with DCM. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase silica gel column chromatography (10% EA / Hex) to obtain 1-((3-fluorophenyl)thio)-2-phenyl-5,6-dihydrocyclopenta[c]pyrrol-4(2H)-one (white solid, 720 mg, yield 85%).

[0817] 1 H NMR (500 MHz, DMSO-d6) δ 7.86 (s, 1 H), 7.42 - 7.47 (m, 3 H), 7.33 - 7.37 (m, 2 H), 7.28 (td,J=8.02, 6.30 Hz, 1 H), 6.96 (td,J=8.59, 1.72 Hz, 1 H), 6.70 - 6.76 (m, 2 H), 2.87 - 2.91 (m, 2 H), 2.82 - 2.86 (m, 2 H); MH + 324

[0818]

[0819] Step 3: 1-((3-fluorophenyl)sulfonyl)-2-phenyl-5,6-dihydrocyclopenta[c]pyrrole-4(2H)-one (147)

[0820] 1-((3-Fluorophenyl)thio)-2-phenyl-5,6-dihydrocyclopenta[c]pyrrole-4(2H)-one (720 mg, 1 eq, 2.23 mmol) was dissolved in DCM (7.4 mL, 0.3 M) and stirred at 0°C for 10 minutes. mCPBA (1.7 g, 4.5 eq, 10.02 mmol) was added at 0°C and stirred at 0°C for 6 hours. After completion of the reaction, sodium thiosulfate aqueous solution was added to terminate the reaction, sodium bicarbonate aqueous solution was added to adjust the pH to 8, and the mixture was extracted twice with DCM. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 1-((3-fluorophenyl)sulfonyl)-2-phenyl-5,6-dihydrocyclopenta[c]pyrrol-4(2H)-one was obtained by purification by normal silica gel column chromatography (50-100% EA / Hex) (yellow gel 557 mg, yield 70%).

[0821] 1 H NMR (500 MHz, DMSO-d6) δ 7.79 (s, 1 H), 7.50 - 7.54 (m, 3 H), 7.40 - 7.44 (m, 2 H), 7.24 - 7.28 (m, 1 H), 7.11 - 7.15 (m, 2 H), 7.00 - 7.04 (m, 1 H), 3.23 - 3.27 (m, 2 H), 2.83 - 2.88 (m, 2 H); MH + 356

[0822]

[0823] Step 4: 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-4-amine (148)

[0824] 1-((3-Fluorophenyl)sulfonyl)-2-phenyl-5,6-dihydrocyclopenta[c]pyrrole-4(2H)-one (557 mg, 1 eq, 1.57 mmol) was dissolved in methanol (39.2 mL, 0.04 M), titanium(IV) isopropoxide (2.4 mL, 5 eq, 7.84 mmol) and 2 M methylamine in THF (7.8 mL, 10 eq, 15.7 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Sodium borohydride (592.9 mg, 10 eq, 15.7 mmol) was slowly added, and the mixture was stirred for 30 minutes. After completion of the reaction, saturated aqueous NaHCO3 solution was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by amino silica gel column chromatography (2% MeOH / MC) to obtain 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-4-amine (yellow gel 565 mg, yield 97%).

[0825] 1 H NMR (500 MHz, DMSO-d6) δ 7.44 - 7.55 (m, 3 H), 7.36 - 7.41 (m, 2 H), 7.21 - 7.25 (m, 1 H), 7.06 - 7.10 (m, 3 H), 6.93 (dt,J=8.16, 2.22 Hz, 1 H), 3.91 (dd,J=7.16, 4.30 Hz, 1 H), 2.99 - 3.06 (m, 1 H), 2.82 - 2.91 (m, 1 H), 2.52 - 2.59 (m, 1 H), 2.28 (s, 3 H), 2.03 - 2.13 (m, 1 H); MH + 371

[0826]

[0827] Step 5: 1-((3-Fluorophenyl)sulfonyl)-N-methyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-4-amine hydrochloride (149)

[0828] 1-((3-Fluorophenyl)sulfonyl)-N-methyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-4-amine was dissolved in ethyl acetate (5.1 mL, 0.3 M) and stirred at 0°C for 2 minutes. 1 M HCl in EA (1.83 mL, 1.2 eq, 1.93 mmol) was added, and the reaction temperature was slowly raised to room temperature. After stirring for 30 minutes, the mixture was filtered to obtain 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-4-amine hydrochloride (white solid 575 mg, yield 93%).

[0829] 1 H NMR (500 MHz, DMSO-d6) δ 9.07 (br s, 1 H), 7.47 - 7.56 (m, 3 H), 7.38 - 7.45 (m, 3 H), 7.24 (dt,J=7.02, 1.65 Hz, 1 H), 7.06 - 7.10 (m, 2 H), 6.96 - 7.00 (m, 1 H), 4.52 (dd,J=8.02, 2.86 Hz, 1 H), 3.14 - 3.22 (m, 1 H), 2.96 - 3.07 (m, 1 H), 2.73 - 2.82 (m, 1 H), 2.57 (s, 3) H), 2.42 - 2.48 (m, 1 H); MS m / z 340 (MH + - NH2Me - HCl)

[0830]

[0831] [Example 50] 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (156) and [Example 51] 3-chloro-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (157)

[0832]

[0833]

[0834] Step 1: tert-Butyl 3-(2-(2-fluorophenyl)-2-oxoethyl)-4-oxopiperidine-1-carboxylate (153)

[0835] tert-Butyl 4-oxopiperidine-1-carboxylate (1 g, 1 eq) and pyrrolidine (0.99 mL, 2.4 eq) were dissolved in benzene (10.04 mL, 0.5 M), the mixture was heated to 100°C, stirred for 6 hours, and then concentrated under reduced pressure. The mixture was dissolved in THF (6.27 mL, 0.8 M), trimethylamine (1.05 mL, 1.5 eq) and 2-bromo-1-(2-fluorophenyl)ethan-1-one (2175 mg, 2 eq) were added, the mixture was heated to 60°C, and stirred for 15 hours. 2-Bromo-1-(2-fluorophenyl)ethan-1-one (543 mg, 0.5 eq) was then added, and the mixture was further stirred at 60°C for 5 hours. The temperature was lowered to 0℃, 0.5 M HCl (10.5 mL) was added, ethyl acetate was added to dilute, and the mixture was washed 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 tert-butyl 3-(2-(2-fluorophenyl)-2-oxoethyl)-4-oxopiperidine-1-carboxylate (790 mg, yield 46%).

[0836] 1 H NMR (500 MHz, DMSO-d6) δ 7.82 (td,J=7.74, 1.75 Hz, 1 H), 7.64 - 7.71 (m, 1 H), 7.32 - 7.40 (m, 2 H), 4.04 - 4.31 (m, 2 H), 3.27 - 3.32 (m, 1 H), 3.15 - 3.26 (m, 1 H), 2.84 - 3.13 (m, 3 H), 2.52 - 2.61 (m, 1 H), 2.26 - 2.33 (m, 1 H), 1.42 (s, 9 H); [M-Boc] + 236

[0837]

[0838] Step 2: tert-Butyl 2-(2-fluorophenyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (154)

[0839] tert-Butyl 3-(2-(2-fluorophenyl)-2-oxoethyl)-4-oxopiperidine-1-carboxylate (790 mg, 1 eq) was dissolved in ethanol (10.44 mL, 0.24 M), ammonium acetate (965 mg, 5 eq) was added, the mixture was heated to 80°C, and stirred for 1 hour. The mixture was diluted with methylene chloride, washed with distilled water, and a saturated aqueous solution of NaHCO3. The extracted organic layer was dried over Na2SO4, and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified with diethyl ether to give tert-butyl 2-(2-fluorophenyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (515 mg, yield 69%).

[0840] 1 H NMR (500 MHz, DMSO-d6) δ 11.00 (br s, 1 H), 7.59 - 7.70 (m, 1 H), 7.09 - 7.27 (m, 3 H), 6.34 (t,J=2.75 Hz, 1 H), 4.32 (br s, 2 H), 3.56 - 3.65 (m, 2 H), 2.65 (br t,J=5.65 Hz, 2 H), 1.42 (s, 9 H); [Mt-butyl] + 261

[0841]

[0842] Step 3: tert-Butyl 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (155)

[0843] A 60% sodium hydride dispersion in mineral oil (34 mg, 1.1 eq) was dissolved in DMF (3.24 mL, 0.4 M), and tert-butyl 2-(2-fluorophenyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (410 mg, 1 eq) dissolved in DMF (3.24 mL, 0.4 M) was added, and the mixture was stirred at room temperature for 1 h. 3-Fluorobenzenesulfonyl chloride (0.34 mL, 2 eq) was added, and the mixture was stirred at room temperature for 2 h 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 tert-butyl 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (47 mg, 7%).

[0844] 1 H NMR (500 MHz, DMSO-d6) δ 7.56 - 7.69 (m, 2 H), 7.44 - 7.52 (m, 1 H), 7.29 - 7.36 (m, 1 H), 7.15 - 7.27 (m, 4 H), 6.33 (s, 1 H), 4.25 (br d,J=1.07 Hz, 2 H), 3.59 (br t,J=5.57 Hz, 2 H), 2.85 - 2.91 (m, 2 H), 1.40 (s, 9 H); [Mt-butyl] + 419

[0845]

[0846] Step 4: 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (156) and 3-chloro-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (157)

[0847] tert-Butyl 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (45 mg, 1 eq) was dissolved in DCM (0.47 mL 0.2 M), trifluoroacetic acid (0.01 mL, 2 eq) was added, and the mixture was stirred at room temperature for 2 h. Afterwards, trifluoroacetic acid (0.01 mL, 2 eq) was additionally added, and the mixture was stirred at room temperature for 17 h. After the temperature was lowered to 0°C, the mixture was neutralized with 1 N NaOH aqueous solution. After diluting with methylene chloride, 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 amino silica gel column chromatography to obtain 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (22 mg, yield 61%). 1 H NMR (500 MHz, DMSO-d6) δ 7.57 - 7.69 (m, 2 H), 7.42 - 7.50 (m, 1 H), 7.29 - 7.34 (m, 1 H), 7.19 - 7.25 (m, 3 H), 7.17 (dt,J=8.24, 2.06 Hz, 1 H), 6.21 (s, 1 H), 3.55 (s, 2 H), 2.87 - 2.92 (m, 2 H), 2.71 - 2.76 (m, 2 H); MH + 375 and 3-chloro-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (2 mg, yield 5%), 1H NMR (500 MHz, DMSO-d6) δ 7.61 - 7.72 (m, 2 H), 7.50 - 7.59 (m, 1 H), 7.35 (dt,J=7.48, 1.53 Hz, 1 H), 7.18 - 7.30 (m, 4 H), 3.47 - 3.60 (m, 2 H), 2.88 - 2.99 (m, 2 H), 2.72 - 2.87 (m, 2 H); MH + 409 was obtained.

[0848]

[0849] [Example 52] 2-(2,4-difluorophenyl)-1-((3,4-difluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (159)

[0850]

[0851]

[0852] 2-(2,4-Difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (200 mg) was dissolved in THF (4.3 mL), and a 60% sodium hydride dispersion in mineral oil (52 mg) was added at 0°C. The reaction mixture was purged with nitrogen and stirred at room temperature for 1 h. 3,4-Difluorobenzenesulfonyl chloride (137 μL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched by adding distilled water at 0°C, and extracted with EA. 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 2-(2,4-difluorophenyl)-1-((3,4-difluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (yellow solid, 245 mg, yield 70%).

[0853] 1H NMR (500 MHz, DMSO-d6) δ 7.58 - 7.71 (m, 2 H), 7.33 - 7.42 (m, 1 H), 7.28 (td,J=9.59, 2.37 Hz, 1 H), 7.03 - 7.19 (m, 2 H), 6.50 (s, 1 H), 3.31 - 3.34 (m, 2 H), 2.82 (dt,J=4.78, 2.12 Hz, 2 H); MH + 410

[0854]

[0855] [Example 53] 2-(2,4-difluorophenyl)-1-((2,4-difluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (161)

[0856]

[0857]

[0858] 2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (150 mg) was added to a solution of 60% sodium hydride dispersion (38.6 mg, 1.5 eq) in THF (3.22 mL) at 0°C, and the mixture was stirred at room temperature for 1 hour. 2,4-Difluorobenzenesulfonyl chloride (95.14 μL, 1.1 eq) was added to the reaction solution at 0°C, and the mixture was stirred at room temperature for 16 hours. After quenching the reaction by adding H2O, the 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 silica gel column chromatography to obtain 2-(2,4-difluorophenyl)-1-((2,4-difluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (yellow oil 162 mg, yield 62%).

[0859] 1H NMR (500 MHz, DMSO-d6) δ 7.70 (ddd,J=11.08, 8.94, 2.45 Hz, 1 H), 7.35 (td,J=8.64, 5.96 Hz, 1 H), 7.20 - 7.28 (m, 2 H), 7.14 (td,J=8.41, 6.72 Hz, 1 H), 7.04 - 7.10 (m, 1 H), 6.56 (s, 1 H), 3.24 (dt,J=4.85, 2.24 Hz, 2 H), 2.88 (dt,J=4.78, 2.27 Hz, 2 H); MH + 410

[0860]

[0861] [Example 54] 1-((3-Acetylphenyl)sulfonyl)-2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (163)

[0862]

[0863]

[0864] 2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (150 mg) was added to a solution of sodium hydride (38.6 mg, 1.5 eq) in THF (3.22 mL) at 0°C, and the mixture was stirred at room temperature for 1 hour. 3-Acetylbenzenesulfonyl chloride (155 mg, 1.1 eq) was added to the reaction solution at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched by adding distilled water, 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 silica gel column chromatography to obtain 1-((3-acetylphenyl)sulfonyl)-2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (ivory solid, 80 mg, yield 30%).

[0865] 1H NMR (500 MHz, DMSO-d6) δ 8.34 (dt,J=7.95, 1.22 Hz, 1 H), 7.93 - 7.99 (m, 1 H), 7.79 (t,J=7.87 Hz, 1 H), 7.74 (t,J=1.68 Hz, 1 H), 7.27 (td,J=9.55, 2.45 Hz, 1 H), 7.16 (td,J=8.33, 6.72 Hz, 1 H), 7.07 - 7.13 (m, 1 H), 6.52 (s, 1 H), 3.34 - 3.37 (m, 2 H), 2.87 (dt,J=4.81, 2.18 Hz, 2 H), 2.58 (s, 3 H); MH + 416

[0866]

[0867] [Example 55] 2-(2-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (171)

[0868]

[0869]

[0870] Step 1: 2-(2-methoxyphenyl)-1H-pyrrole (165)

[0871] To a solution of tert-butyl 2-bromo-1H-pyrrole-1-carboxylate (30 mmol) in toluene (80 mL), H2O (10 mL), and MeOH (10 mL) were added 2-methoxyphenylboronic acid (5.44 g, 1.2 eq), a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1.12 g, 0.05 eq), and K2CO3 (8.24 g, 2.0 eq), and stirred at 80°C for 16 h. The reaction solution was filtered through celite ®It was filtered using. After adding ethyl acetate and diluting, it was washed several times with distilled water and brine. The extracted organic layer was dried using Na2SO4 and filtered under reduced pressure. The reactant was dissolved in THF (100 mL), and then 30 mL of sodium methoxide (Ca. 30% w / w in MeOH) was added and stirred at room temperature for 1 hour. The reaction solution 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 phase silica gel column chromatography to obtain 2-(2-methoxyphenyl)-1H-pyrrole (green oil 4.24 g, yield 82%). MH + 174

[0872]

[0873] Step 2: 5-(2-methoxyphenyl)-1H-pyrrole-2-carbaldehyde (166)

[0874] 2-(2-methoxyphenyl)-1H-pyrrole (4.24 g) was dissolved in DMF (2.84 mL, 1.5 eq). The solution was cooled to -78°C, phosphorus(V) oxychloride (3.43 mL, 1.5 eq) was slowly added, and the mixture was stirred at -20°C for 40 min. A solution of NaOH (2.94 g, 3.0 eq) dissolved in H2O (15 mL) was slowly added dropwise to the reaction solution, and the mixture was stirred at 110°C for 40 min. The reaction solution 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 silica gel column chromatography to obtain 5-(2-methoxyphenyl)-1H-pyrrole-2-carbaldehyde (brown oil 3.6 g, yield 73%).

[0875] 1H NMR (500 MHz, DMSO-d6) δ 11.74 - 11.90 (m, 1 H), 9.52 (s, 1 H), 7.77 (dd,J=7.72, 1.60 Hz, 1 H), 7.34 (ddd,J=8.52, 7.22, 1.68 Hz, 1 H), 7.14 (dd,J=8.41, 0.76 Hz, 1 H), 7.05 (dd,J=3.90, 2.37 Hz, 1 H), 7.02 (td,J=7.53, 0.99 Hz, 1 H), 6.78 (dd,J=3.97, 2.29 Hz, 1 H), 3.89 (s, 3 H); MH + 202

[0876]

[0877] Step 3: Ethyl (E)-3-(5-(2-methoxyphenyl)-1H-pyrrol-2-yl)acrylate (167)

[0878] A solution of triethyl phosphonoacetate (4.26 mL, 1.2 eq) and Cs2CO3 (8.74 g, 1.5 eq) in 1,4-dioxane (89 mL) and H2O (0.89 mL) was stirred at room temperature for 30 minutes. 5-(2-methoxyphenyl)-1H-pyrrole-2-carbaldehyde (3.6 g) was added to the reaction solution and stirred at 80°C for 16 hours. The reaction solution 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 ethyl (E)-3-(5-(2-methoxyphenyl)-1H-pyrrol-2-yl)acrylate (brown oil, 3.5 g, yield 70%).

[0879] 1H NMR (500 MHz, DMSO-d6) δ 7.68 (dd,J=7.72, 1.60 Hz, 1 H), 7.56 (d,J=15.89 Hz, 1 H), 7.23 - 7.29 (m, 1 H), 7.10 (dd,J=8.25, 0.92 Hz, 1 H), 7.00 (td,J=7.49, 1.07 Hz, 1 H), 6.69 (ddd,J=12.84, 3.67, 2.45 Hz, 2 H), 6.36 (d,J=15.89 Hz, 1 H), 4.14 (q,J=7.03 Hz, 2 H), 3.88 (s, 3H), 1.24 (t,J=7.11 Hz, 3 H); MH + 272

[0880]

[0881] Step 4: Ethyl 3-(5-(2-methoxyphenyl)-1H-pyrrol-2-yl)propanoate (168)

[0882] To a solution of ethyl (E)-3-(5-(2-methoxyphenyl)-1H-pyrrol-2-yl)acrylate (3.5 g) in ethanol (65 mL), 10% palladium on carbon (42 mg, 0.03 eq) was added and stirred at room temperature for 4 hours under hydrogen conditions. The reaction solution was transferred to Celite ® After filtration under reduced pressure using , the filtrate was concentrated under reduced pressure to obtain ethyl 3-(5-(2-methoxyphenyl)-1H-pyrrol-2-yl)propanoate (yellow oil 3.17 g, yield 96%). MH + 274

[0883]

[0884] Step 5: 3-(5-(2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid (169)

[0885] Ethyl 3-(5-(2-methoxyphenyl)-1H-pyrrol-2-yl)propanoate (3.17 g) was dissolved in a mixed solvent of THF (30 mL) and H2O (10 mL), and KOH (1.3 g, 2.0 eq) was added. The mixture was stirred at 80°C for 4 hours. The reaction solution was diluted with ethyl acetate and the pH was adjusted to 2–3. The solution was 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 3-(5-(2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid (brown oil, 2.68 g, yield 94%).

[0886] 1 H NMR (500 MHz, DMSO-d6) δ 10.60 (br s, 1 H), 7.56 (dd,J=7.72, 1.60 Hz, 1 H), 7.10 (dd,J=7.03, 1.38 Hz, 1 H), 7.02 (dd,J=8.25, 0.92 Hz, 1 H), 6.94 (dd,J=7.49, 1.07 Hz, 1 H), 6.43 - 6.47 (m, 1 H), 5.83 (dd,J=3.21, 2.60 Hz, 1 H), 3.86 (s, 3 H), 2.79 - 2.87 (m, 2 H), 2.56 (t,J=7.57 Hz, 2 H), 1.91 (s, 3 H); MH + 245

[0887]

[0888] Step 6: 2-(2-methoxyphenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (170)

[0889] Polyphosphoric acid (10.95 g, 3.0 eq) was placed in a round-bottomed flask and heated to 100°C. 3-(5-(2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid (2.68 g) was added to the resulting solution and stirred at 100°C for 4 hours. The reaction solution was dissolved in methanol, alkalized with an aqueous NaHCO3 solution, and washed several times with ethyl acetate, distilled water, and brine. 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 then concentrated under reduced pressure. The concentrated reaction product was solidified using CH2Cl2 and hexane, and then filtered under reduced pressure to obtain 2-(2-methoxyphenyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one (brown solid, 210 mg, yield 8.5%).

[0890] 1 H NMR (500 MHz, DMSO-d6) δ 11.62 (br s, 1 H), 7.61 (dd,J=7.79, 1.68 Hz, 1 H), 7.26 (ddd,J=8.44, 7.14, 1.68 Hz, 1 H), 7.10 (dd,J=8.25, 0.92 Hz, 1 H), 6.99 (td,J=7.53, 1.15 Hz, 1 H), 6.57 (d,J=1.99 Hz, 1 H), 3.88 (s, 3 H), 2.92 - 2.95 (m, 2 H), 2.72 - 2.75 (m, 2 H); MH + 228

[0891]

[0892] Step 7: 2-(2-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (171)

[0893] 2-(2-Methoxyphenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (210 mg, 1 eq, 0.92 mmol) was dissolved in DMF (4.6 mL, 0.2 M) and stirred for 5 minutes under nitrogen at 0°C. A 60% sodium hydride dispersion in mineral oil (55.4 mg, 1.5 eq, 1.50 mmol) was added and stirred for 1 hour. 3-Fluorobenzenesulfonyl chloride (135.2 μL, 1.1 eq, 1.02 mmol) was added and stirred at room temperature for 2 hours. After completion of the reaction, NaHCO3(aq) was added at 0°C to terminate the reaction and extracted twice with ethyl acetate. Sodium sulfate was added to the organic layer, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by normal silica gel column chromatography (50-100% EA / Hex) to obtain 2-(2-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one (brown solid, 26 mg, yield 7.3%).

[0894] 1 H NMR (500 MHz, DMSO-d6) δ 7.60 - 7.67 (m, 2 H), 7.43 - 7.47 (m, 1 H), 7.36 - 7.38 (m, 1 H), 7.18 - 7.20 (m, 1 H), 6.92 - 6.96 (m, 3 H), 6.29 (s, 1 H), 3.30 - 3.32 (m, 2 H), 2.83 - 2.85 (m, 2 H); MH + 386

[0895]

[0896] [Example 56] 1-((3-fluorophenyl)sulfonyl)-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (6)

[0897]

[0898]

[0899] 2-Phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (300 mg, 1 eq, 1.42 mmol) was dissolved in DMF (3.6 mL, 0.4 M), and a 60% sodium hydride dispersion in mineral oil (227 mg, 4 eq, 5.68 mmol) was added and stirred at room temperature for 30 minutes. 3-Fluorobenzenesulfonyl chloride (757 μL, 4 eq, 5.68 mmol) was added and stirred at room temperature for 1 hour. After completion of the reaction, H2O was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by amino silica gel column chromatography (EA / Hex 20-50%) to obtain 1-((3-fluorophenyl)sulfonyl)-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one (80 mg of pink solid, yield 15%).

[0900] 1 H NMR (500 MHz, DMSO-d6) δ 7.57 - 7.72 (m, 2 H), 7.38 - 7.45 (m, 1 H), 7.29 - 7.37 (m, 3 H), 7.20 (br d,J=7.45 Hz, 1 H), 7.10 - 7.17 (m, 2 H), 6.41 - 6.46 (m, 1 H), 3.24 (br d,J=4.58 Hz, 2 H), 2.41 - 2.47 (m, 2 H), 2.13 (br d,J=5.73 Hz, 2 H); MH + 370

[0901]

[0902] [Experimental Example 1] Preparation of gastric vesicles

[0903] The gastrointestinal vesicles used in the experiment were separated by centrifugation (Saccomani G, et al., A Nonelectrogenic H +Pump in Plasma Membranes of Hog Stomach, J Biol Chem., 1976, 251(23), 7690~8) was isolated and prepared from the porcine gastric mucosa. Afterwards, the protein contents of the gastrointestinal vesicles were quantified using a BCA (Bicinchoninic Acid) kit (Smith PK, et al., Measurement of protein using bicinchoninic acid, Anal Biochem., 1985, 150(1), 76~85).

[0904]

[0905] [Experimental Example 2] Proton pump (H + / K + Measurement of inhibitory effect on ATPase activity

[0906] Inhibitory effect on proton pump activity is K + K excluding pump activity in the absence of ions +The pump activity in the presence of ions was calculated based on the inhibitory effect on proton pump activity. The inhibitory effect on proton pump activity was measured in a 96-well plate, and all reactions were performed at 37°C in a reaction volume of 100 μL. 10 μM valinomycin and compounds at various concentrations were added to the reaction buffer (50 mmol / L Tris-Hepes buffer, pH 6.5 or pH 7.4, 5 mM MgCl2, 5 mM KCl) containing porcine gastrointestinal vesicles, and the cells were preincubated for 20 minutes. 1% DMSO was added to the negative and positive controls in the buffer, and 1% DMSO and compounds at various concentrations were diluted and added to the test groups. Subsequently, 0.2 mmol / L adenosine triphosphate (ATP) was added to the reaction buffer, and the cells were incubated at 37°C for 40 minutes. After incubation, a solution of malachite green was added to the reaction buffer and incubated for an additional 30 minutes. The amount of inorganic phosphate was measured by a colorimetric method (Malachite Green Phosphate Assay Kit, Bioassay Systems). For colorimetric measurement, the optical density (OD) value was measured at 620 nm using a microplate reader (FilterMax F5 Multi-Mode Microplate Readers, Molecular Devices). Proton pump (H + / K + The inhibition rate for -ATPase was derived from the OD value of the control group and the OD values ​​of various concentrations of the test compound, and the IC of the test compound 50 was calculated using nonlinear regression analysis in the GraphPad Prism 9 program.

[0907]

[0908] [Experimental Example 3] Sodium-potassium pump (Na + / K + Measurement of inhibitory effect on ATPase activity

[0909] Inhibitory effect on sodium-potassium pump activity + , K + Na excluding pump activity in the absence of ions + , K + Calculation was made based on the pump activity in the presence of ions. The inhibitory effect on the sodium-potassium pump activity was measured in a 96-well plate, and all reactions were performed at 37°C in a reaction volume of 100 μL. Na + , K + -ATPase (porcine cerebral cortex) was purchased from Sigma and used. Na + , K + -Compounds of each concentration were added to a reaction buffer containing ATPase (50 mmol / L Tris-Hepes buffer, pH 7.5, 100 mM NaCl, 2 mM MgCl2, 5 mM KCl) and incubated for 20 minutes. 1% DMSO was added to the buffer for the negative and positive controls, and 1% DMSO and a diluted version of each compound of each concentration were added to the test group. Subsequently, 0.2 mmol / L adenosine triphosphate (ATP) was added to the reaction buffer and incubated at 37°C for 40 minutes. After incubation, the amount of inorganic phosphate was measured by colorimetric method (Malachite Green Phosphate Assay Kit, Bioassay Systems) by adding malachite green solution to the reaction buffer and incubating for an additional 30 minutes. For colorimetric measurement, the optical density (OD) value was measured at 620 nm using a microplate reader (FilterMax F5 Multi-Mode Microplate Readers, Molecular Devices). Sodium-potassium pump (Na + / K +The inhibition rate for -ATPase was derived from the OD value of the control group and the OD values ​​of various concentrations of the test compound, and the IC of the test compound 50 second It was calculated using nonlinear regression analysis in the GraphPad Prism 9 program.

[0910]

[0911] The measurement results of Test Examples 2 and 3 are shown in Tables 1 to 3 below.

[0912]

[0913] H + / K + -ATPase IC 50 (μM) - pH 6.5 Compound IC 50 (μM) Compound IC 50 (μM) Compound IC 50 (μM) Example 12.85 Example 210.14 Example 410.78 Example 22.05 Example 220.18 Example 420.061 Example 30.085 Example 230.086 Example 430.048 Example 40.072 Example 240.096 Example 450.046 Example 50.037 Example 250.093 Example 467.1 Example 60.026 Example 260.12 Example 470.025 Example 70.037 Example 270.11 Example 483.6 Example 80.12 Example 280.12 Example 490.51 Embodiment 90.097 Embodiment 290.13 Embodiment 50>10 Embodiment 100.096 Embodiment 300.084 Embodiment 51>10 Embodiment 110.039 Embodiment 310.087 Embodiment 120.054 Embodiment 320.58 Embodiment 130.083 Embodiment 330.11 Embodiment 140.066 Embodiment 340.19 Embodiment 150.053 Embodiment 350.069 Embodiment 160.050 Embodiment 360.086 Embodiment 170.16 Embodiment 370.081 Embodiment 181.09 Embodiment 380.15 Embodiment 190.093 Example 390.14 Example 200.15 Example 400.35

[0914]

[0915] H + / K + -ATPase IC 50 (μM) - pH 7.4 Compound IC 50 (μM) Compound IC 50 (μM) Compound IC 50 (μM) Example 40.11 Example 220.49 Example 380.27 Example 90.19 Example 250.12 Example 390.20 Example 140.15 Example 260.16 Example 400.74 Example 150.13 Example 270.20 Example 410.99 Example 170.26 Example 360.22 Example 490.93 Example 190.22 Example 370.15

[0916]

[0917] Na + / K + -ATPase IC 50 (μM) - pH 7.5 Compound IC 50 (μM) Compound IC 50 (μM) Compound IC 50 (μM) Example 3 > 100 Example 19 > 100 Example 37 > 100 Example 4 > 100 Example 20 > 100 Example 38 > 100 Example 8 > 100 Example 21 > 100 Example 39 > 100 Example 9 > 100 Example 22 > 100 Example 40 > 100 Example 10 > 100 Example 2561.83 Example 41 > 100 Example 1477.24 Example 2659.98 Example 49 > 100 Example 1569.03 Example 36 > 100

[0918]

[0919] As shown in Tables 1 to 3 above, the compounds of the present invention have gastric H + / K + -Has an excellent inhibitory effect on ATPase, and Na + / K + -It was confirmed to be selective for ATPase.

[0920]

[0921] [Experimental Example 4] Inhibitory effect on esophageal damage in a reflux esophagitis model

[0922] To evaluate the inhibitory effect of the compound of the example on esophageal damage in rats with reflux esophagitis induced by refluxed gastric acid, the following procedure was performed.

[0923] Male Sprague-Dawley rats were fasted for 18 h with only water. Under isoflurane anesthesia, the abdominal cavity of the rats was incised, and the pyloric region and the junction between the anterior stomach and the body of the stomach were additionally ligated to allow gastric acid reflux into the esophagus. Immediately after ligation, the control group received intraduodenal administration of 5 mL / kg of a 0.5% methylcellulose (MC) solution, while the other groups received intraduodenal administration of 10.0 mg / kg / 5 mL of the test compound suspended in 0.5% MC solution. Six hours after ligation, the test animals were sacrificed, and the excised esophagus was incised longitudinally and fixed to expose the mucosal portion. The esophageal lesion area was analyzed using Image J software (NIH, Bethesda).

[0924]

[0925] % inhibitory activity of test compound = {(total esophageal damage area of ​​control group - esophageal damage area of ​​test compound-treated group) / total esophageal damage area of ​​control group} Х 100

[0926]

[0927] The results are shown in Table 4 below.

[0928]

[0929] Compound dose inhibitory activity (%), n=3 Example 4 10 mpk 100 % Example 9 10 mpk 100 % Example 15 10 mpk 100 % Example 19 10 mpk 100 % Example 22 10 mpk 100 % Example 25 10 mpk 100 % Example 26 10 mpk 100 % Example 37 10 mpk 87.1 %

[0930] As shown in Table 4 above, it was confirmed that the compounds of the present invention have a strong esophageal damage inhibitory effect in a reflux esophagitis model.

Claims

1. A compound represented by the following chemical formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof: (I) Here X 1 , X 2 and X 3 are each independently C or N, at least one of which is N; L is a single bond, sulfonyl, C 1-6 Alkylene, or C 1-6 It is alkylenesulfonyl; R 1 , R 2 and R 3 are each independently H, halogen, C 6-15 Aryl, C 3-15 Cycloalkyl, 5-15 membered heteroaryl, or 3-15 membered heterocycloalkyl, wherein aryl, cycloalkyl, 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; A is C 1-3 Methylene substituted or unsubstituted with alkylamino or oxo; Y is CH2 or NH; n is an integer from 0 to 3.

2. In paragraph 1, X 1 , X 2 and X 3 One or two of them are N and the rest are C; L is a single bond or sulfonyl; R 1 and R 2 are each independently H, halogen, C 6-12 Aryl, C 3-12 Cycloalkyl, 5-12 membered heteroaryl, or 3-12 membered heterocycloalkyl, wherein aryl, cycloalkyl, 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 3 is H or halogen; A is C 1-3 Methylene substituted or unsubstituted with alkylamino or oxo; Y is CH2 or NH; A compound wherein n is an integer from 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. In paragraph 2, X 1 , X 2 and X 3 One or two of them are N and the rest are C; R 1 Silver H, halogen, C 6-12 Aryl, 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 with or without one or more substituents selected from the group consisting of alkoxy and acetyl, wherein said heteroaryl and heterocycloalkyl each independently contain one or two heteroatoms selected from the group consisting of N, S and O; R 2 is C 6-12 Aryl or 5-12 membered heteroaryl, wherein aryl and heteroaryl are each independently halogen, C 1-6 Alkoxy and C 1-6 A compound having or not having one or more substituents selected from alkyl, wherein said heteroaryl contains one or two heteroatoms each independently selected from the group consisting of N, S and O, or a pharmaceutically acceptable salt or stereoisomer thereof.

4. In paragraph 1, The residue of the above chemical formula (I) Is or and; A is C 1-6 Methylene substituted or unsubstituted with alkylamino or oxo; Y is CH2 or NH; A compound wherein n is an integer from 0 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof.

5. In paragraph 1, The residue of the above chemical formula (I) Is , , , , or and; X 1 , X 2 and X 3 One or two of them are N and the rest are C; Z is C 1-3 An alkyl compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

6. In paragraph 1, The residue of the above chemical formula (I) Is , , , , , or , and Z is C 1-3 An alkyl group, compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

7. 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 , R B , and R C are each independently H, hydroxy, halogen, cyano, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 A compound selected from the group consisting of alkoxy and acetyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

8. In paragraph 1, R 2 Is or and; M is independently CH or N, and at least one M is N; R A , R B , and R C are each independently H, halogen, C 1-6 Alkyl, and C 1-6 A compound selected from the group consisting of alkoxy, or a pharmaceutically acceptable salt or stereoisomer thereof.

9. In paragraph 1, X 1 , X 2 and X 3 Of these, one is N and the other two are C; L is a single bond or sulfonyl; R 1 is phenyl, pyridyl, indolyl, dihydrobenzodioxinyl, furanyl, or imidazolyl, wherein phenyl, pyridyl, indolyl, dihydrobenzodioxinyl, furanyl, and imidazolyl each independently have or do not have one or two substituents selected from the group consisting of hydroxy, halogen, cyano, methyl, halomethyl, methoxy, methoxypropoxy, and acetyl; R 2 is phenyl or pyridyl, wherein phenyl and pyridyl each independently have or do not have one to two substituents selected from the group consisting of halogen, methoxy and methyl; R 3 is H or halogen; A is methylene, optionally substituted with methylamino, ethylamino or oxo; Y is CH2 or NH; n is 1 or 2, a compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

10. In paragraph 1, R 1 Silver H, , , , , , , , , , , , , , , , , , or A compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

11. In paragraph 1, R 2 Is , , , , , , or A compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

12. In paragraph 1, A compound selected from the group consisting of: or a pharmaceutically acceptable salt or stereoisomer thereof; 1> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-4,5,6,7-tetrahydro-1H-indol-4-amine; 2> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-4,5,6,7-tetrahydro-1H-indol-4-amine hydrochloride; 3> 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 4> 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride; 5> 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine fumarate; 6> 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine 2,3-dihydroxysuccinate; 7> 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine adipate; 8> 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 9> 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride; 10> 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine 2-hydroxysuccinate; 11> 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine adipate; 12> 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine fumarate; 13> 2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine maleate; 14> 1-((3-chlorophenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride; 15> 1-((3-methoxyphenyl)sulfonyl)-2-(2-fluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride; 16> 3-((2-(2-fluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)phenol hydrochloride; 17> 2-(2-fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride; 18> N-Ethyl-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 19> 2-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride; 20> 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 21> 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine fumarate; 22> 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride; 23> 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine (2E,4E)-hexa-2,4-dienoate; 24> 2-(2,4-difluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine adipate; 25> 1-((3-chlorophenyl)sulfonyl)-2-(2,4-difluorophenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride; 26> 2-(2,4-difluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride; 27> 3-((2-(2,4-difluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)phenol hydrochloride; 28> 3-((2-(2,4-difluorophenyl)-4-(methylamino)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)sulfonyl)benzonitrile; 29> 2-(2,4-difluorophenyl)-N-methyl-1-((1-methyl-1H-indol-4-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 30> 2-(2,4-difluorophenyl)-N-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 31> 2-(2,4-difluorophenyl)-1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 32> 2-(2,4-difluorophenyl)-1-(furan-2-ylsulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 33> 2-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 34> 2-(2,4-difluorophenyl)-N-methyl-1-((6-methylpyridin-3-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 35> 2-(2,4-difluorophenyl)-1-((3,4-dimethylphenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 36> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 37> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride; 38> N-Methyl-2-phenyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 39> N-Methyl-2-phenyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride; 40> N-Methyl-1-((1-methyl-1H-indol-4-yl)sulfonyl)-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride; 41> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-(pyridin-3-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine dihydrochloride; 42> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-(o-tolyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 43> 2-(3-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 44> 2-(2,4-difluorophenyl)-N-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 45> (R)-2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 46> (S)-2-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine; 47> (R)-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride; 48> (S)-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-amine hydrochloride; 49> 1-((3-fluorophenyl)sulfonyl)-N-methyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrol-4-amine hydrochloride; 50> 2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 51> 3-Chloro-2-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 52> 2-(2,4-difluorophenyl)-1-((3,4-difluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one; 53> 2-(2,4-difluorophenyl)-1-((2,4-difluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one; 54> 1-((3-Acetylphenyl)sulfonyl)-2-(2,4-difluorophenyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one; 55> 2-(2-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H)-one; and 56> 1-((3-Fluorophenyl)sulfonyl)-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one.

13. 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 12, or a pharmaceutically acceptable salt or stereoisomer thereof, as an active ingredient.

14. In paragraph 13, A pharmaceutical composition wherein the disease related to the above gastric acid secretion is selected from the group consisting of gastrointestinal disease, dyspepsia, functional dyspepsia, gastroesophageal disease, 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 12, or a pharmaceutically acceptable salt or stereoisomer thereof, for the prevention or treatment of diseases related to gastric acid secretion.

16. In paragraph 15, The above-mentioned disease related to gastric acid secretion is selected from the group consisting of gastrointestinal disease, dyspepsia, functional dyspepsia, gastroesophageal disease, 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, and is used for the prevention or treatment of a disease related to gastric acid secretion.

17. Use of a compound of formula (I) according to any one of claims 1 to 12, 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.

18. In paragraph 17, The above-mentioned gastric acid secretion-related diseases are 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, and use for the manufacture of a medicament for the prevention or treatment of diseases related to gastric acid secretion.

19. 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 12, or a pharmaceutically acceptable salt or stereoisomer thereof.

20. In paragraph 19, A method for preventing or treating a disease related to gastric acid secretion, wherein the disease related to gastric acid secretion is selected from the group consisting of gastrointestinal disease, dyspepsia, functional dyspepsia, gastroesophageal disease, 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.