4-cyclopropyl pyrrole derivative and use thereof

Abstract

The present invention relates to: a novel 4-cyclopropyl pyrrole derivative exhibiting proton pump inhibitory activity and, more specifically, to a 4-cyclopropyl pyrrole derivative exhibiting excellent proton pump inhibitory activity or a pharmaceutically acceptable salt thereof; and a use thereof for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.

Description

4-Cyclopropylpyrrole derivatives and uses thereof

[0001] The present invention relates to a novel 4-cyclopropyl pyrrole derivative exhibiting proton pump inhibitory activity, and more particularly, to a 4-cyclopropyl pyrrole derivative exhibiting excellent proton pump inhibitory activity or a pharmaceutically acceptable salt thereof, and its use in the prevention or treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0002] The proton pump is the final step in a series of gastric acid secretion reactions that occur when various acid secretion stimulants (histamine, acetylcholine, gastrin, etc.) bind to receptors present in the gastric parietal cells in the body. + and release K + H that absorbs + / K + -ATPase enzyme. Therefore, proton pump inhibitors (PPIs) inhibit H in the parietal cells, the final stage of gastric acid secretion. + / K + -It is a drug that inhibits gastric acid secretion by inhibiting ATPase, and its effect on gastric acid secretion is more effective and lasts longer than that of existing drugs, so it has been widely used for the treatment of peptic ulcers, gastric and duodenal ulcers, gastritis, and gastroesophageal reflux disease (GERD) for the past 20 years. In particular, the treatment rate for gastroesophageal reflux disease, an inflammatory disease that causes esophageal cancer (adenocarcinoma) through Barrett's esophagus if left chronically untreated, has improved rapidly since the launch of proton pump inhibitors (PPIs).

[0003] However, conventional proton pump inhibitors (PPIs) are activated by acid secretion to form sulphenamide, which is then released into the H + / K +-It has been pointed out that it can cause side effects such as proliferation of bacteria in the stomach, promotion of proton pump expression, and possibility of tumor cell formation due to hypergastrinemia by irreversibly binding to the cysteine ​​residue of -ATPase and suppressing gastric acid secretion for a long period of time [Havu N, Digestion, 1986, 35(Suppl 1), 42~55; Chang Seok Song, Dong Il Park, Korean J Med., 2011, 81(1), 6~10], and recently, it has been confirmed that it increases the risk of hip, wrist, and spine fractures by inhibiting calcium absorption ability and bone cell growth through gastric acid suppression when used for a long period of time [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, with the increase in the use of nonsteroidal anti-inflammatory drugs (NSAIDs) due to the increase in the aging population and the improvement in survival rates for various diseases due to the advancement of various medical technologies, the number of patients with peptic ulcers and gastroesophageal reflux disease (GERD) of various causes is increasing. Despite the highly effective treatment ability of proton pump inhibitors (PPIs), the number of patients who are refractory to PPIs is also rapidly increasing.

[0004] Therefore, among the recent drugs that suppress gastric acid secretion, H + / K +There is growing interest in and need for potassium competitive acid blockers (P-CABs, acid pump antagonists), which reversibly bind to the K-binding site of ATPase and inhibit acid secretion through potassium-competitive inhibition. In particular, unlike irreversible proton pump inhibitors (PPIs), reversible proton pump inhibitors (P-CABs) exhibit rapid onset of action due to their mechanism of action, are easy to take regardless of mealtime, and are expected to be highly effective in alleviating nocturnal symptoms, a problem with irreversible proton pump inhibitors.

[0005] The development of P-CABs was first reported in a paper in 1982. The first drug in this class was SCH28080, developed by Schering-Plough. SCH28080 was more effective in suppressing gastric acid secretion than omeprazole, a representative PPI, but further development was halted due to toxic effects on the liver. Another drug is Linaprazan, developed by AstraZeneca, which is an H + / K +-It was reported to be a potent reversible inhibitor of ATPase. In phase 2 and 3 clinical trials, Linaprazan showed similar efficacy to the PPI drug Esomeprazole in treating esophagitis and improving symptoms of gastroesophageal reflux disease. However, this drug's development was discontinued due to hepatotoxicity caused by reversible elevation of hepatic transaminases. Nycomed's Soraprazan was proven to be more effective than PPIs in preclinical and early clinical trials, but its development was discontinued in phase 2b clinical trials, although the reason was not disclosed. The first P-CAB to pass rigorous clinical trials and be commercialized was Revanex (Revaprazan, KR 10-0157075 B1), developed by Yuhan Corporation and approved in Korea in 2005. Revaprazan, like other P-CABs, showed rapid onset of action, but was not superior to existing PPIs. In particular, it was not applied for approval for gastroesophageal reflux disease due to its poor efficacy. The second commercialized P-CAB was Takecab (Vonoprazan fumarate, KR 10-1115857 B1), which was approved in Japan by Takeda in 2015. This drug demonstrated superior properties compared to PPIs, including a rapid onset of action, a long duration of action, and consistent and potent acid suppression; however, it was reported to be less effective in Westerners. The third commercialized P-CAB drug is K-CAB (Tegoprazan, KR 10-1088247 B1), which was originally developed by RaQualia in Japan and licensed to CJ Healthcare (now HK inno&) in Korea, and was approved in Korea in 2019 and is now being sold. Additionally, Daewoong Pharmaceutical's Fexuclue (Fexuprazan, KR 10-1613245 B1) is currently on sale, and Jeil Pharmaceutical's JAQBO (Zastaprazan, KR 10-1777971 B1) has also completed clinical trials and received approval.

[0006] Accordingly, the present inventors conducted research to develop a low-molecular-weight reversible proton pump inhibitor (P-CAB) that can be useful in the prevention or treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases such as peptic ulcer, gastric / duodenal ulcer, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD), and as a result, prepared a novel compound, a 4-cyclopropyl pyrrole derivative, and confirmed that the compound exhibited excellent proton pump inhibitory activity, thereby completing the present invention.

[0007] The present invention aims to provide a 4-cyclopropyl pyrrole derivative or a pharmaceutically acceptable salt thereof exhibiting excellent proton pump inhibitory activity.

[0008] In addition, another object of the present invention is to provide a pharmaceutical composition for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases, comprising the 4-cyclopropyl pyrrole derivative or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.

[0009] In addition, another object of the present invention is to provide a use of the 4-cyclopropyl pyrrole derivative or a pharmaceutically acceptable salt thereof in the prevention or treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0010] In addition, another object of the present invention is to provide a method for preventing or treating gastrointestinal inflammatory disease or gastric acid-related disease by administering the 4-cyclopropyl pyrrole derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0011] In one aspect of the present invention, a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided:

[0012] [Chemical Formula 1]

[0013]

[0014]

[0015] In the above chemical formula 1, R 1 and R 2 is as defined herein.

[0016] In another aspect of the present invention, a pharmaceutical composition for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases is provided, comprising a therapeutically effective amount of a compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.

[0017] In another aspect of the present invention, the use of the compound of formula 1 or a pharmaceutically acceptable salt thereof in the prevention or treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases is provided.

[0018] The compound according to the present invention, i.e., a 4-cyclopropyl pyrrole derivative or a pharmaceutically acceptable salt thereof, has excellent proton pump inhibitory activity and gastric damage inhibition rate. Therefore, the 4-cyclopropyl pyrrole derivative or a pharmaceutically acceptable salt thereof can be effectively applied to the prevention or treatment of damage caused by reflux esophagitis, gastritis, gastrointestinal ulcers, etc.

[0019] Hereinafter, the present invention will be described in detail.

[0020]

[0021] According to one aspect of the present invention, a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided:

[0022] [Chemical Formula 1]

[0023]

[0024]

[0025] In the above chemical formula 1,

[0026] R 1is aryl, partially unsaturated heterocyclyl or heteroaryl; wherein said aryl, partially unsaturated heterocyclyl and heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy, haloalkoxy, cycloalkoxy, cycloalkyl-alkoxy and heteroaryl;

[0027] R 2 is aryl or heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy, haloalkyl and heteroaryl;

[0028] The above partially unsaturated heterocyclyl and heteroaryl have one or more heteroatoms selected from N, O and S.

[0029]

[0030] Unless otherwise specified, the following terms used in the present invention have the meanings set forth below. Any undefined term has the meaning understood in the art.

[0031] In the present invention, the term “halo” or “halogen”, when used alone or in combination with other additional terms (e.g., haloalkyl), means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0032] As used herein, the term “alkyl”, when used alone or in combination with other additional terms (e.g., haloalkyl), means a radical of a straight or branched saturated aliphatic hydrocarbon group having, for example, 1 to 7 or 1 to 5 carbon atoms. Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl.

[0033] In the present invention, the term “alkoxy” means an alkyloxy (-O-alkyl group), for example, an alkyloxy having 1 to 7 or 1 to 5 carbon atoms.

[0034] As used herein, the term “cycloalkyl” refers to a saturated aliphatic hydrocarbon radical having, for example, 3 to 10 carbon atoms or 3 to 8 carbon atoms in a ring shape. Typical examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0035] In the present invention, the term “cycloalkoxy” means cycloalkyloxy (-O-cycloalkyl group), for example, cycloalkyloxy having 3 to 10 or 3 to 8 carbon atoms.

[0036] In the present invention, the term “aryl” means an aromatic hydrocarbon having, for example, 6 to 10 carbon atoms, and specific examples include, but are not limited to, phenyl and naphthyl.

[0037] In the present invention, the term “heteroaryl” means an aromatic hydrocarbon having 5 to 12 members or 5 to 10 members and containing one or more heteroatoms selected from N, O and S as a reducing group.

[0038] In the present invention, the term “partially unsaturated heterocyclyl” means a cyclic, for example, 5 to 12-membered or 8 to 12-membered, partially unsaturated hydrocarbon containing one or more heteroatoms selected from N, O and S as a reducing group.

[0039]

[0040] According to one specific example of the present invention, in the chemical formula 1

[0041] R 1 Silver C6-C 10 Aryl, partially unsaturated 5 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl; wherein said aryl, partially unsaturated heterocyclyl and heteroaryl are halo, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, C3-C 10 Cycloalkoxy, C3-C 10 which may be optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl-C1-C7alkoxy and 5 to 12 membered heteroaryl;

[0042] R 2 is C6-C 10 Aryl or 5 to 12 membered heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkyl and 5 to 12 membered heteroaryl;

[0043] The above partially unsaturated heterocyclyl and heteroaryl may have 1 to 3 heteroatoms selected from N, O and S.

[0044] According to another specific embodiment of the present invention,

[0045] R 1is C6 aryl, partially unsaturated 8 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl; wherein said aryl, partially unsaturated heterocyclyl and heteroaryl may be optionally substituted with one or two substituents selected from the group consisting of halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkoxy, C3-C8 cycloalkoxy, C3-C8 cycloalkyl-C1-C5 alkoxy and 5 to 10 membered heteroaryl;

[0046] The above partially unsaturated heterocyclyl and heteroaryl may have 1 to 3 heteroatoms selected from N and O.

[0047] According to another specific embodiment of the present invention,

[0048] R 2 is C6 aryl or 5 to 10 membered heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with 1 or 2 substituents selected from the group consisting of halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkyl and 5 to 10 membered heteroaryl;

[0049] The above heteroaryl may have 1 to 3 heteroatoms selected from N and O.

[0050] According to another specific embodiment of the present invention,

[0051] R 1 is C6 aryl, partially unsaturated 9 or 10 membered heterocyclyl or 6 to 10 membered heteroaryl; wherein said aryl, partially unsaturated heterocyclyl and heteroaryl may be optionally substituted with one or two substituents selected from the group consisting of halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkoxy, C3-C8 cycloalkyl-C1-C5 alkoxy and 5 or 6 membered heteroaryl;

[0052] The above partially unsaturated heterocyclyl and heteroaryl may have one or two heteroatoms selected from N and O.

[0053] According to another specific embodiment of the present invention,

[0054] R 2 is C6 aryl, or 5 or 6 membered heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with 1 or 2 substituents selected from the group consisting of halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkyl and 5 or 6 membered heteroaryl;

[0055] The above heteroaryl may have one or two heteroatoms selected from N and O.

[0056] According to another specific example of the present invention, the chemical formula 1 may be the following chemical formula 1-1:

[0057] [Chemical Formula 1-1]

[0058]

[0059] In the above chemical formula 1-1,

[0060] R 2 is as defined in chemical formula 1;

[0061] R 3 and R 4 are each independently -H, halo, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, C3-C 10 Cycloalkoxy, C3-C 10 Cycloalkyl-C1-C7alkoxy or 5 to 12 membered heteroaryl;

[0062] The above heteroaryl may have 1 to 3 heteroatoms selected from N, O and S.

[0063] According to another specific example of the present invention, in the chemical formula 1-1

[0064] R 3 and R 4are each independently -H, halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkoxy, C3-C8 cycloalkyl-C1-C5 alkoxy, or 5 or 6 membered heteroaryl;

[0065] The above heteroaryl may have one or two heteroatoms selected from N and O.

[0066] According to another specific example of the present invention, in the chemical formula 1-1

[0067] R 2 is C6 aryl, or 5 or 6 membered heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with 1 or 2 substituents selected from the group consisting of halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkyl and 5 or 6 membered heteroaryl;

[0068] The above heteroaryl may have one or two heteroatoms selected from N and O.

[0069] According to another specific example of the present invention, the chemical formula 1 may be any one selected from the following chemical formulas 1-2 to 1-8:

[0070] [Chemical Formula 1-2]

[0071]

[0072] [Chemical Formula 1-3]

[0073]

[0074] [Chemical Formula 1-4]

[0075]

[0076] [Chemical Formula 1-5]

[0077]

[0078] [Chemical Formula 1-6]

[0079]

[0080] [Chemical Formula 1-7]

[0081]

[0082] [Chemical Formula 1-8]

[0083]

[0084] In the above chemical formulas 1-2 to 1-8,

[0085] R 2 is as defined in chemical formula 1;

[0086] R 3 and R 4 are each independently -H, halo, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, C3-C 10 Cycloalkoxy, C3-C 10 Cycloalkyl-C1-C7alkoxy or 5 to 12 membered heteroaryl;

[0087] The above heteroaryl may have 1 to 3 heteroatoms selected from N, O and S.

[0088] According to another specific example of the present invention, in the chemical formulas 1-2 to 1-8,

[0089] R 3 and R 4 are each independently -H, halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkoxy, C3-C8 cycloalkyl-C1-C5 alkoxy, or 5 or 6 membered heteroaryl;

[0090] The above heteroaryl may have one or two heteroatoms selected from N and O.

[0091]

[0092] According to another embodiment of the present invention, the pharmaceutically acceptable salt may be, but is not limited to, hydrochloride, phosphate, fumarate, citrate, tartrate or succinate.

[0093]

[0094] According to another specific example of the present invention, representative examples of the compounds of the above chemical formula 1 may include, but are not limited to, the following compounds:

[0095] 1) 1-(4-cyclopropyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0096] 2) 1-(4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-phenyl-1H-pyrrol-3-yl)-N-methylmethanamine;

[0097] 3) 1-(4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0098] 4) 1-(4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0099] 5) 1-(4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0100] 6) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0101] 7) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0102] 8) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine fumarate;

[0103] 9) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine 2-hydroxypropane-1,2,3-tricarboxylate;

[0104] 10) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine phosphate;

[0105] 11) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine succinate;

[0106] 12) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine 2,3-dihydroxysuccinate;

[0107] 13) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0108] 14) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0109] 15) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0110] 16) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0111] 17) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0112] 18) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0113] 19) 1-(1-((4-(1H-pyrazol-1-yl)phenyl)sulfonyl)-4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0114] 20) 1-(4-cyclopropyl-5-(4-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0115] 21) 1-(5-(4-(1H-pyrrol-1-yl)phenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl-N-methylmethanamine;

[0116] 22) 1-(4-cyclopropyl-5-(2-fluoro-4-(1H-pyrrol-1-yl)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0117] 23) 1-(4-cyclopropyl-5-(4-(cyclopropylmethoxy)-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0118] 24) 1-(4-cyclopropyl-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0119] 25) 1-(4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0120] 26) 1-(4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0121] 27) 1-(4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0122] 28) 1-(4-cyclopropyl-5-(2,4-difluorophenyl)1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0123] 29) 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0124] 30) 1-(4-Cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methylpyridin-3-yl)-sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0125] 31) 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl-1H-pyrrol-3-yl)-N-methylmethanamine;

[0126] 32) 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride;

[0127] 33) 1-(4-cyclopropyl-5-(2-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0128] 34) 1-(4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-methoxyphenyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0129] 35) 1-(4-Cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0130] 36) 1-(4-cyclopropyl-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0131] 37) 1-(4-Cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0132] 38) 1-(4-Cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyrimidin-5-yl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0133] 39) 1-(4-Cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(quinoxalin-6-yl)-1H-pyrrol-3-yl)-N-methylmethanamine;

[0134] 40) 1-(4-cyclopropyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; and

[0135] 41) 1-(5-(2-Chlorophenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine.

[0136]

[0137] The compound represented by the above chemical formula 1 can be prepared by a method as shown in the following reaction scheme 1.

[0138] [Reaction Formula 1]

[0139]

[0140]

[0141] In the above reaction scheme 1, R 1 and R 2 is as defined above.

[0142]

[0143] In addition, the compound represented by chemical formula 2 of the above reaction scheme 1 can be prepared by the same method as reaction scheme 2.

[0144] [Reaction Formula 2]

[0145]

[0146]

[0147] In the above reaction formula 2, R 1 is as defined above.

[0148]

[0149] First, the preparation of the compound of the above chemical formula 2 can be performed by Steps I-1 to I-4 of the method represented by Reaction Scheme 2.

[0150] The above step I-1 is a step of preparing a compound represented by chemical formula 9 by reacting methyl 2-(dimethoxyphosphoryl)acetate represented by chemical formula 7 with a compound represented by chemical formula 8. The above reaction can be performed in an organic solvent such as tetrahydrofuran.

[0151] The above step I-2 is a step of preparing a compound represented by the above chemical formula 10 by reacting the compound represented by the above chemical formula 9 with (para-toluenesulfonyl)methyl isocyanide, which is a pyrrole cyclization reaction step. The above reaction can be performed in an organic solvent such as dimethyl sulfoxide or diethyl ether.

[0152] The above step I-3 is a step of producing a compound represented by the above chemical formula 11 by brominating the compound represented by the above chemical formula 10. The above reaction can be performed using a reagent such as N-bromosuccinimide (NBS), which can introduce bromine to the hydrogen position of pyrrole of the compound represented by the above chemical formula 10. In addition, the above reaction can be performed in an organic solvent such as tetrahydrofuran.

[0153] The above step I-4 is a step for preparing a compound represented by the above chemical formula 2 by bonding a phenyl group substituted with various substituents to the compound represented by the above chemical formula 11. A typical palladium (Pd) catalyst can be used as the metal catalyst. The above reaction can be carried out in an organic solvent such as toluene, 1,4-dioxane, or tetrahydrofuran, or a polar solvent such as water.

[0154]

[0155] Next, a compound represented by the chemical formula 1 can be prepared by the above reaction scheme 1. The method represented by the above reaction scheme 1 can be performed by II-1 to II-4.

[0156] The above step II-1 is a step of preparing a compound represented by the above chemical formula 4 by reacting the compound represented by the above chemical formula 2 with the compound represented by the above chemical formula 3. This step is a step of introducing an arylsulfonyl group substituted to the pyrrole group of the compound represented by the above chemical formula 2. The above reaction can be carried out in an organic solvent such as acetonitrile or tetrahydrofuran in the presence of sodium hydride or dimethylaminopyridine.

[0157] The above step II-2 is a step of producing a compound represented by the above chemical formula 5 by reducing the methyl ester group of the compound represented by the above chemical formula 4 to an alcohol group. The reduction can be performed using a reducing agent such as diisobutyl aluminum hydride (DIBAL-H) ​​in an organic solvent such as tetrahydrofuran.

[0158] The above step II-3 is a step of oxidizing the compound represented by the above chemical formula 5 to prepare the compound represented by the above chemical formula 6. The oxidation of the alcohol group of the compound represented by the above chemical formula 5 can be performed in an organic solvent such as dichloromethane using an oxidizing agent such as manganese dioxide (MnO2) or pyridinium chlorochromate (PCC).

[0159] The above step II-4 is a step of producing a compound represented by the above chemical formula 1 by reacting the compound represented by the above chemical formula 6 with methylamine, and is a reductive amination reaction step. The reductive amination can be performed using sodium borohydride (NaBH4) in an organic solvent such as methanol.

[0160]

[0161] If necessary, an acid such as hydrochloric acid, phosphoric acid, fumaric acid, citric acid, tartaric acid, succinic acid, etc. may be added to the compound represented by the chemical formula 1 prepared as described above to prepare a pharmaceutically acceptable acid addition salt such as a hydrochloride salt, a phosphate salt, a fumarate salt, a citrate salt, a tartrate salt, or a succinic acid salt. This can be done by diluting hydrochloric acid or fumaric acid in an organic solvent such as methanol, adding dropwise the compound represented by the chemical formula 1 diluted in an organic solvent such as ethyl acetate, and reacting for 2 hours to prepare an acid addition salt.

[0162]

[0163] According to another aspect of the present invention, a pharmaceutical composition for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases is provided, comprising a therapeutically effective amount of a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, together with a pharmaceutically acceptable carrier.

[0164]

[0165] According to another specific example of the present invention, the gastrointestinal inflammatory disease or gastric acid-related disease may be, but is not limited to, gastrointestinal ulcer, gastritis, or reflux esophagitis.

[0166]

[0167] According to another specific embodiment of the present invention, the pharmaceutically acceptable carrier may be a commonly used excipient, disintegrant, sweetener, lubricant, or flavoring agent. The pharmaceutical composition of the present invention may be formulated into oral preparations such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups, or parenteral preparations such as injections, according to a conventional method. The preparation may be formulated into various forms, for example, single-dose or multiple-dose dosage forms.

[0168] The composition may be administered orally or parenterally, including intravenously, intramuscularly, intraperitoneally, subcutaneously, rectally, and topically. The composition is preferably administered orally. Accordingly, the composition may be formulated in various forms, such as tablets, capsules, aqueous solutions, or suspensions. For oral tablets, carriers such as lactose and corn starch and lubricants such as magnesium stearate may typically be added. For oral capsules, lactose and / or dried corn starch may be used as diluents. If an oral aqueous suspension is required, the active ingredient may be combined with an emulsifier and / or suspending agent. If desired, certain sweeteners and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous, and intravenous administration, a sterile solution of the active ingredient is typically prepared, and the pH of the solution should be suitably adjusted and buffered. For intravenous administration, the total concentration of the solute must be adjusted to impart isotonicity to the formulation. The composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline with a pH of 7.4. The solution may be introduced into the patient's intramuscular bloodstream via local bolus injection.

[0169] At this time, the pharmaceutical composition may be administered in a therapeutically effective amount. Accordingly, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition may be administered to the patient in an effective amount of about 0.01 mg / kg to about 100 mg / kg per day. Of course, the dosage may vary depending on the patient's age, weight, sensitivity, symptoms, or the efficacy of the compound.

[0170]

[0171] Example

[0172] The present invention is described in detail below through examples and test examples. However, the following examples and test examples are intended to illustrate the present invention and are not intended to limit the present invention.

[0173]

[0174] Analysis of the compounds prepared in the following examples: Nuclear magnetic resonance (NMR) spectroscopy was performed on a JEOL 400 MHz spectrometer, chemical shifts were analyzed in ppm, and mass spectrometry was performed using an LC / MS (Acquity UPLC system / Xevo-TQ MS) system based on Waters UPLC. Column chromatography was performed on silica gel (Merck, 70-230 mesh), and reagents used in each example were purchased from Sigma-Aldrich and TCI.

[0175]

[0176] Example 1: Preparation of 1-(4-cyclopropyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0177]

[0178]

[0179] Step 1-1: Preparation of methyl 3-cyclopropyl acrylate

[0180] Trimethylphosphonoacetate (100.0 g, 0.549 mol) was added to 1.5 L of tetrahydrofuran, cooled to 0°C, and sodium hydride (25 g, 0.604 mol) was slowly added. After stirring at room temperature for 30 minutes, cyclopropanecarboxaldehyde (42.3 g, 0.604 mol) was added and reacted for 1 hour and 30 minutes. After cooling the reaction mixture to 0°C, purified water was slowly added, and extracted twice with ethyl acetate. The obtained extract was treated with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (61.4 g, yield: 88.6%).

[0181] 1 H-NMR (400 MHz, DMSO-d 6 ): 6.41-6.35 (q, 1H), 5.95-5.91 (d, 1H), 3.60 (s, 3H), 1.67-1.58 (m, 1H), 0.96-0.84 (m, 2H), 0.66-0.60 (m, 2H).

[0182]

[0183] Step 1-2: Preparation of methyl 4-cyclopropyl-1H-pyrrole-3-carboxylate

[0184] Sodium hydride (38.9 g, 0.973 mol) was added to 800 mL of diethyl ether and cooled to 0°C. Methyl 3-cyclopropyl acrylate (61.4 g, 0.487 mol) and p-toluenesulfonylmethyl isocyanide (104.5 g, 0.535 mol), prepared in step 1-1 above, were dissolved in 400 mL of dimethyl sulfoxide, added dropwise, and stirred for 1 hour. Purified water was slowly added to the reaction mixture and extracted three times with ethyl acetate. The obtained extract was treated with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3), followed by crystallization with diethyl ether to obtain the title compound (59.3 g, yield: 73.6%).

[0185] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.09 (s, 1H), 7.26-7.24 (m, 1H), 6.41-6.40 (t, 1H), 3.66 (s, 3H), 2.18-2.11 (m, 1H), 0.76-0.71 (m, 2H), 0.43-0.39 (m, 2H).

[0186]

[0187] Step 1-3: Preparation of methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate

[0188] Methyl 4-cyclopropyl-1H-pyrrole-3-carboxylate (5 g, 0.030 mol) prepared in the above step 1-2 was dissolved in 80 mL of tetrahydrofuran and cooled to 0°C. N-bromosuccinimide (5.11 g, 0.029 mol) was slowly added to the cooled solution, stirred for 20 minutes, purified water was added, and extracted with ethyl acetate. The obtained extract was treated with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and used immediately in the next reaction.

[0189]

[0190] Step 1-4: Preparation of methyl 4-cyclopropyl-5-phenyl-1H-pyrrole-3-carboxylate

[0191] Methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.030 mol) prepared in the above step 1-3 was dissolved in 80 mL of 1,4-dioxane, and then phenylboronic acid (4.42 g, 0.036 mol), 20 mL of purified water, potassium carbonate (10.43 g, 0.076 mol), and Pd(dppf)Cl2 (1.22 g, 0.002 mol) were sequentially added and stirred under reflux for 2 hours. After cooling the reaction to room temperature, purified water was added, and extracted with ethyl acetate. The obtained extract was treated with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to obtain the title compound (7.26 g, yield: 99.6%).

[0192] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.51 (s, 1H), 7.55 (s, 1H), 7.41-7.37 (t, 3H), 7.28-7.25 (m, 2H), 3.69 (s, 3H), 1.89-1.85 (m, 1H), 0.77-0.72 (m, 2H), 0.10-0.06 (m, 2H).

[0193]

[0194] Step 1-5: Preparation of methyl 4-cyclopropyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

[0195] Methyl 4-cyclopropyl-5-phenyl-1H-pyrrole-3-carboxylate (1.4 g, 0.006 mol) prepared in the above steps 1-4 was dissolved in 50 mL of tetrahydrofuran, cooled to 0°C, sodium hydride (0.35 g, 0.009 mol) was slowly added, and stirred for 30 minutes. Pyridine-3-sulfonyl chloride (1.55 g, 0.009 mol) was added dropwise to the reaction mixture and stirred for 1 hour. After adding purified water, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to obtain the title compound (2.0 g, yield: 90.1%).

[0196] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.85-8.83 (dd, 1H), 8.40-8.39 (m, 1H), 8.03 (s, 1H), 7.84-7.81 (m, 1H), 7.56-7.53 (qd, 1H), 7.45-7.41 (tt, 1H), 7.32-7.29 (m, 2H), 6.98-6.96 (m, 2H), 3.78 (s, 3H), 1.78-1.71 (m, 1H), 0.46-0.41 (m, 2H), 0.07-0.03 (m, 2H).

[0197]

[0198] Step 1-6: Preparation of (4-cyclopropyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol

[0199] Methyl 4-cyclopropyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (2.0 g, 0.005 mol) prepared in the above steps 1-5 was dissolved in 50 mL of tetrahydrofuran, cooled to -50°C, and diisobutylaluminum hydride (1.0 M toluene solution) (21 mL, 0.021 mol) was added dropwise. After stirring at room temperature for 2 hours, cooled to 0°C, purified water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain the title compound (1.73 g, yield: 93.5%).

[0200] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.82-8.80 (dd, 1H), 8.38-8.37 (m, 1H), 7.74-7.71 (m, 1H), 7.66-7.63 (m, 1H), 7.56-7.53 (qd, 1H), 7.41-7.30 (m, 3H), 7.03-6.99 (m, 2H), 4.39-4.38 (m, 2H), 1.43-1.36 (m, 1H), 0.44-0.39 (m, 2H), 0.14-0.10 (m, 2H).

[0201]

[0202] Step 1-7: Preparation of 4-cyclopropyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0203] (4-Cyclopropyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol (1.73 g, 0.005 mol) prepared in the above steps 1-6 was dissolved in 50 mL of acetonitrile, and then tetrapropylammonium perruthenate (0.26 g, 0.001 mol) and N-methylmorpholine N-oxide (1.32 g, 0.011 mol) were added and stirred for 1 hour. The reaction mixture was concentrated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:2) to obtain the title compound (0.8 g, yield: 46.5%).

[0204] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.91 (s, 1H), 8.86-8.84 (dd, 1H), 8.42-8.41 (m, 1H), 8.40 (s, 1H), 7.83-7.80 (m, 1H), 7.58-7.55 (m, 1H), 7.45-7.41 (m, 1H), 7.33-7.30 (m, 2H), 6.99-6.97 (m, 2H), 1.68-1.63 (m, 1H), 0.51-0.46 (m, 2H), 0.28-0.24 (m, 2H).

[0205]

[0206] Step 1-8: Preparation of 1-(4-cyclopropyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0207] 4-Cyclopropyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.8 g, 0.002 mol) prepared in the above steps 1-7 was dissolved in 30 mL of tetrahydrofuran, and methylamine (2 M tetrahydrofuran solution) (3.5 mL, 0.007 mol) was added and stirred for 5 hours. Sodium borohydride (0.52 g, 0.014 mol) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 9:1) to obtain the title compound (0.35 g, yield: 42.0%).

[0208] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.82-8.80 (dd, 1H), 8.39-8.38 (m, 1H), 7.74-7.71 (m, 1H), 7.56-7.53 (m, 1H), 7.41-7.37 (m, 2H), 7.34-7.30 (m, 2H), 7.04-7.00 (m, 2H), 3.62 (s, 2H), 2.36 (s, 3H), 1.45-1.41 (m, 1H), 0.45-0.40 (m, 2H), 0.05-0.01 (m, 2H).

[0209] [M+H] + : 367.99

[0210]

[0211] Example 2: Preparation of 1-(4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-phenyl-1H-pyrrol-3-yl)-N-methylmethanamine

[0212]

[0213]

[0214] Step 2-1: Preparation of methyl 4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-phenyl-1H-pyrrole-3-carboxylate

[0215] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-phenyl-1H-pyrrole-3-carboxylate (4.0 g, 0.017 mol) and 6-methylpyridine-3-sulfonyl chloride (4.77 g, 0.025 mol) prepared in step 1-4 above (5.38 g, yield: 82.0%).

[0216] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.26-8.25 (d, 1H), 8.01 (s, 1H), 7.71-7.69 (dd, 1H), 7.46-7.39 (m, 2H), 7.34-7.30 (m, 2H), 7.00-6.97 (m, 2H), 3.77 (s, 3H), 2.53 (s, 3H), 1.76-1.71 (m, 1H), 0.46-0.41 (m, 2H), 0.06-0.02 (m, 2H).

[0217]

[0218] Step 2-2: Preparation of (4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-phenyl-1H-pyrrol-3-yl)methanol

[0219] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-phenyl-1H-pyrrole-3-carboxylate (5.38 g, 0.014 mol) prepared in step 2-1 above (4.24 g, yield: 85.0%).

[0220] 1 H-NMR (400 MHz, DMSO-d 6): 8.26-8.25 (d, 1H), 7.61-7.59 (dd, 1H), 7.41-7.37 (m, 2H), 7.35-7.30 (m, 3H), 7.07-7.03 (m, 2H), 4.97-4.94 (t, 1H), 4.38-4.37 (d, 2H), 2.52 (s, 3H), 1.42-1.37 (m, 1H), 0.44-0.39 (m, 2H), 0.14-0.10 (m, 2H).

[0221]

[0222] Step 2-3: Preparation of 4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

[0223] The title compound was prepared in the same manner as in step 1-7 using 4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-phenyl-1H-pyrrol-3-yl)methanol (4.24 g, 0.012 mol) prepared in step 2-2 above (3.11 g, yield: 74.0%).

[0224] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.90 (s, 1H), 8.38 (s, 1H), 8.28-8.27 (d, 1H), 7.70-7.68 (dd, 1H), 7.46-7.41 (m, 2H), 7.35-7.31 (m, 2H), 7.01-6.99 (m, 2H), 1.69-1.62 (m, 1H), 0.51-0.46 (m, 2H), 0.28-0.24 (m, 2H).

[0225]

[0226] Step 2-4: Preparation of 1-(4-cyclopropyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0227] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (1.0 g, 0.003 mol) prepared in step 2-3 above (0.45 g, yield: 43.3%).

[0228] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.28-8.27 (d, 1H), 7.62-7.60 (dd, 1H), 7.50-7.40 (m, 3H), 7.39-7.31 (m, 2H), 7.07-7.01 (m, 2H), 3.64 (s, 2H), 2.51 (s, 3H), 2.37 (s, 3H), 1.47-1.40 (m, 1H), 0.48-0.37 (m, 2H), 0.04-0.01 (m, 2H).

[0229] [M+H] + : 382.01

[0230]

[0231] Example 3: Preparation of 1-(4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0232]

[0233]

[0234] Step 3-1: Preparation of methyl 4-cyclopropyl-5-(o-tolyl)-1H-pyrrole-3-carboxylate

[0235] The title compound was prepared in the same manner as in step 1-4 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.024 mol) and 2-methylphenylboronic acid (3.94 g, 0.029 mol) prepared in step 1-3 above (1.55 g, yield: 25.0%).

[0236] 1 H-NMR (400 MHz, DMSO-d 6): 11.24 (s, 1H), 7.33-7.32 (d, 1H), 7.27-7.26 (m, 2H), 7.22-7.17 (m, 2H), 3.68 (s, 3H), 2.14 (s, 3H), 1.89-1.82 (m, 1H), 0.50-0.46 (m, 2H), 0.07-0.03 (m, 2H).

[0237]

[0238] Step 3-2: Preparation of methyl 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(o-tolyl)-1H-pyrrole-3-carboxylate

[0239] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(o-tolyl)-1H-pyrrole-3-carboxylate (2.09 g, 0.008 mol) and pyridine-3-sulfonyl chloride (2.18 g, 0.012 mol) prepared in step 3-1 above (2.29 g, yield: 70.0%).

[0240] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.88-8.86 (dd, 1H), 8.39-8.38 (d, 1H), 8.07 (s, 1H), 7.86-7.83 (m, 1H), 7.58-7.55 (qd, 1H), 7.37-7.33 (td, 1H), 7.17-7.10 (m, 2H), 6.80-6.78 (m, 1H), 3.78 (s, 3H), 1.76-1.72 (m, 1H), 1.63 (s, 3H), 0.49-0.45 (m, 1H), 0.37-0.34 (m, 1H), 0.12-0.03 (m, 2H).

[0241]

[0242] Step 3-3: Preparation of (4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)methanol

[0243] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(o-tolyl)-1H-pyrrole-3-carboxylate (2.29 g, 0.006 mol) prepared in step 3-2 above (1.13 g, yield: 54.0%).

[0244] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.84-8.83 (dd, 1H), 8.38-8.37 (m, 1H), 7.76-7.73 (m, 1H), 7.58-7.55 (m, 1H), 7.36 (s, 1H), 7.33-7.29 (td, 1H), 7.18-7.16 (m, 1H), 7.14-7.10 (t, 1H), 6.78-6.76 (dd, 1H), 5.74 (s, 3H), 4.99-4.97 (t, 1H), 4.41-4.40 (m, 2H), 1.32-1.28 (m, 1H), 0.42-0.35 (m, 2H), 0.16-0.13 (m, 2H).

[0245]

[0246] Step 3-4: Preparation of 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(o-tolyl)-1H-pyrrole-3-carbaldehyde

[0247] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)methanol (1.13 g, 0.003 mol) prepared in step 3-3 above (0.83 g, yield: 74.0%).

[0248] 1 H-NMR (400 MHz, DMSO-d 6): 9.00 (s, 1H), 8.89-8.88 (dd, 1H), 8.44 (s, 1H), 8.41-8.40 (m, 1H), 7.85-7.82 (m, 1H), 7.60-7.57 (m, 1H), 7.38-7.34 (td, 1H), 7.18-7.11 (m, 2H), 6.82-6.80 (dd, 1H), 1.65 (s, 3H), 1.63-1.56 (m, 1H), 0.56-0.51 (m, 1H), 0.44-0.38 (m, 1H), 0.30-0.27 (m, 2H).

[0249]

[0250] Step 3-5: Preparation of 1-(4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0251] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(o-tolyl)-1H-pyrrole-3-carbaldehyde (0.83 g, 0.002 mol) prepared in step 3-4 above (0.38 g, yield: 44.2%).

[0252] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.85-8.83 (m, 1H), 8.40-8.39 (m, 1H), 7.76-7.73 (m, 1H), 7.58-7.55 (m, 1H), 7.44 (s, 1H), 7.36-7.30 (m, 1H), 7.18-7.10 (m, 2H), 6.77-6.74 (m, 1H), 3.62 (s, 2H), 2.32-2.31 (d, 3H), 1.71 (s, 3H), 1.39-1.32 (m, 1H), 0.46-0.32 (m, 2H), 0.09-0.03 (m, 2H).

[0253] [M+H] + : 381.95

[0254]

[0255] Example 4: Preparation of 1-(4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0256]

[0257]

[0258] Step 4-1: Preparation of methyl 4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-(o-tolyl)-1H-pyrrole-3-carboxylate

[0259] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(o-tolyl)-1H-pyrrole-3-carboxylate (2.66 g, 0.010 mol) and 6-methylpyridine-3-sulfonyl chloride (3.00 g, 0.016 mol) prepared in step 3-1 above (2.2 g, yield: 51.4%).

[0260] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.24-8.23 (d, 1H), 8.04 (s, 1H), 7.73-7.70 (dd, 1H), 7.42-7.40 (d, 1H), 7.37-7.33 (td, 1H), 7.17-7.11 (m, 2H), 6.81-6.79 (dd, 1H), 3.77 (s, 3H), 2.54 (s, 3H), 1.75-1.70 (m, 1H), 1.65 (s, 3H), 0.51-0.44 (m, 1H), 0.38-0.31 (m, 1H), 0.13-0.02 (m, 2H).

[0261]

[0262] Step 4-2: Preparation of (4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)methanol

[0263] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-(o-tolyl)-1H-pyrrole-3-carboxylate (2.2 g, 0.005 mol) prepared in step 4-1 above (1.52 g, yield: 74.0%).

[0264] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.25-8.24 (d, 1H), 7.64-7.61 (dd, 1H), 7.42-7.40 (d, 1H), 7.33 (s, 1H), 7.31-7.29 (dd, 1H), 7.19-7.11 (m, 2H), 6.80-6.78 (dd, 1H), 4.98-4.96 (t, 1H), 4.40-4.38 (d, 2H), 2.53 (s, 3H), 1.30 (m, 1H), 0.42-0.35 (m, 2H), 0.16-0.13 (m, 2H).

[0265]

[0266] Step 4-3: Preparation of 4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-(o-tolyl)-1H-pyrrole-3-carbaldehyde

[0267] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)methanol (1.52 g, 0.004 mol) prepared in step 4-2 above (1.41 g, yield: 93.4%).

[0268] 1 H-NMR (400 MHz, DMSO-d 6): 9.73 (s, 1H), 8.84-8.82 (m, 1H), 8.46-8.43 (dd, 1H), 7.59-7.57 (d, 1H), 7.52-7.49 (d, 1H), 7.37-7.26 (m, 3H), 7.06 (s, 1H), 2.57 (s, 3H), 2.54 (s, 3H), 2.28-2.17 (m, 1H), 1.18-0.93 (m, 4H).

[0269]

[0270] Step 4-4: Preparation of 1-(4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0271] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-(o-tolyl)-1H-pyrrole-3-carbaldehyde (1.41 g, 0.004 mol) prepared in step 4-3 above (0.42 g, yield: 28.8%).

[0272] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.26-8.25 (d, 1H), 7.63-7.60 (m, 1H), 7.42-7.40 (m, 2H), 7.33-7.29 (m, 1H), 7.19-7.10 (m, 2H), 6.78-6.75 (m, 1H), 3.66 (s, 2H), 2.53 (s, 3H), 2.40 (s, 3H), 1.72 (s, 3H), 1.37-1.33 (m, 1H), 0.42-0.35 (m, 2H), 0.06-0.03 (m, 2H).

[0273] [M+H] + : 396.01

[0274]

[0275] Example 5: Preparation of 1-(4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0276]

[0277]

[0278] Step 5-1: Preparation of methyl 4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(o-tolyl)-1H-pyrrole-3-carboxylate

[0279] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(o-tolyl)-1H-pyrrole-3-carboxylate (6.0 g, 0.024 mol) and 3-fluorophenylsulfonyl chloride (5.49 g, 0.028 mol) prepared in step 3-1 above (4.19 g, yield: 43.1%).

[0280] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.06 (s, 1H), 7.65-7.55 (m, 2H), 7.36-7.33 (td, 1H), 7.30-7.27 (dt, 1H), 7.17-7.09 (m, 3H), 6.83-6.81 (m, 1H), 3.78 (s, 3H), 1.74-1.72 (m, 1H), 1.63 (s, 3H), 0.50-0.45 (m, 1H), 0.36-0.33 (m, 1H), 0.12-0.04 (m, 2H).

[0281]

[0282] Step 5-2: Preparation of (4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)methanol

[0283] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(o-tolyl)-1H-pyrrole-3-carboxylate (4.15 g, 0.010 mol) prepared in step 5-1 above (3.65 g, yield: 94.3%).

[0284] 1 H-NMR (400 MHz, DMSO-d 6): 7.62-7.55 (m, 2H), 7.35 (s, 1H), 7.33-7.29 (td, 1H), 7.25-7.22 (m, 1H), 7.18-7.10 (m, 2H), 7.03-7.00 (m, 1H), 6.80-6.78 (dd, 1H), 2.33 (s, 3H), 1.71 (s, 3H), 1.35-1.32 (m, 1H), 0.42-0.31 (m, 2H), 0.08-0.06 (m, 2H).

[0285]

[0286] Step 5-3: Preparation of 4-cyclopropyl-1-((3-fluorophenyl)-5-(o-tolyl)-1H-pyrrole-3-carbaldehyde

[0287] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)methanol (3.60 g, 0.009 mol) prepared in step 5-2 above (1.86 g, yield: 52.0%).

[0288] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.90 (s, 1H), 8.43 (s, 1H), 7.63-7.60 (m, 2H), 7.36-7.29 (m, 2H), 7.18-7.09 (m, 3H), 6.85-6.83 (dd, 1H), 1.66 (s, 3H), 1.59-1.58 (m, 1H), 0.54-0.53 (m, 1H), 0.41 (m, 1H), 0.31-0.30 (m, 2H).

[0289]

[0290] Step 5-4: Preparation of 1-(4-cyclopropyl-1-((3-fluorophenyl)-5-(o-tolyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0291] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-1-((3-fluorophenyl)-5-(o-tolyl)-1H-pyrrole-3-carbaldehyde (1.81 g, 0.005 mol) prepared in step 5-3 above (0.73 g, yield: 38.8%).

[0292] 1 H-NMR (400 MHz, DMSO-d 6 ): 7.62-7.55 (m, 2H), 7.35-7.29 (m, 2H), 7.25-7.22 (m, 1H), 7.18-7.10 (m, 2H), 7.03-7.00 (m, 1H), 6.80-6.78 (m, 1H), 3.54-3.53 (d, 2H), 2.33 (s, 3H), 1.71 (s, 3H), 1.35-1.32 (m, 1H), 0.42-0.31 (m, 2H), 0.08-0.06 (m, 2H).

[0293] [M+H] + : 398.98

[0294]

[0295] Example 6: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0296]

[0297]

[0298] Step 6-1: Preparation of methyl 4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate

[0299] The title compound was prepared in the same manner as in step 1-4 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (1.088 mol) and 2-fluorophenylboronic acid (228 g, 1.632 mol) prepared in step 1-3 above (139.4 g, yield: 49.3%).

[0300] 1 H-NMR (400 MHz, DMSO-d6 ): 11.50 (s, 1H), 7.44-7.38 (m, 3H), 7.30-7.23 (m, 2H), 3.70 (s, 3H), 1.87-1.83 (m, 1H), 0.62-0.59 (m, 2H), 0.06-0.04 (m, 2H).

[0301]

[0302] Step 6-2: Preparation of methyl 4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

[0303] Methyl 4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (139.4 g, 0.538 mol) prepared in the above step 6-1 was dissolved in 1.1 L of acetonitrile, and then triethylamine (108.8 g, 1.075 mol) and 4-(dimethylamino)pyridine (13.2 g, 0.108 mol) were added. Pyridine-3-sulfonyl chloride (143.2 g, 0.807 mol) was added and stirred for 40 minutes, then purified water was added and stirred for 2 hours. The resulting solid was filtered, dissolved in dichloromethane, treated with brine, dried over anhydrous sodium sulfate, added with activated carbon, and stirred. After 2 hours, the solution was filtered through a diatomaceous earth pad, and the filtrate was concentrated. Ethyl acetate was added to the concentrated residue, hexane was added, the mixture was stirred for 2 hours, and the resulting solid was filtered to obtain the title compound (193.2 g, yield: 89.7%).

[0304] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.89-8.87 (dd, 1H), 8.50-5.49 (d, 1H), 8.12 (s, 1H), 7.95-7.92 (dq, 1H), 7.61-7.51 (m, 2H), 7.211-7.13 (m, 2H), 7.08-7.04 (td, 1H), 3.72 (s, 3H), 1.77-1.73 (m, 1H), 0.50-0.45 (m, 2H), 0.10-0.06 (m, 2H).

[0305]

[0306] Step 6-3: Preparation of (4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol

[0307] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (50.0 g, 0.125 mol) prepared in step 6-2 above.

[0308] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.85-8.83 (dd, 1H), 8.51-8.50 (dd, 1H), 7.85-7.82 (m, 1H), 7.61-7.58 (m, 1H), 7.50-7.48 (m, 1H), 7.42 (s, 1H), 7.22-7.15 (m, 2H), 7.08-7.04 (m, 1H), 5.02-5.00 (t, 1H), 4.46-4.39 (d, 2H), 1.40-1.36 (m, 1H), 0.45-0.43 (m, 2H), 0.18-0.16 (m, 2H).

[0309]

[0310] Step 6-4: Preparation of 4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0311] Pyridinium chlorochromate (80.8 g, 0.375 mol) was dissolved in 500 mL of dichloromethane, and 80.8 g of diatomaceous earth was added. The concentrated residue of (4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol prepared in step 6-3 above was dissolved in 250 mL of dichloromethane, added dropwise, and stirred for 1 hour. The reactant was filtered through a pad of diatomaceous earth, and the filtrate was treated with purified water, 1 N aqueous hydrochloric acid solution, and brine in that order. The organic layer was dried over anhydrous sodium sulfate, and then activated carbon and silica gel were added and stirred. After 2 hours, the filtrate was filtered through a pad of diatomaceous earth, and the filtrate was concentrated. Ethyl acetate was added to the concentrated residue, hexane was added, the mixture was stirred for 2 hours, and the resulting solid was filtered to obtain the title compound (20.3 g, yield: 43.9%-2 steps).

[0312] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.90 (s, 1H), 8.90-8.89 (dd, 1H), 8.52-8.51 (d, 1H), 8.48 (s, 1H), 7.93-7.90 (m, 1H), 7.63-7.60 (m, 1H), 7.58-7.52 (m, 1H), 7.22-7.15 (m, 2H), 7.09-7.05 (td, 1H), 1.70-1.63 (m, 1H), 0.54-0.46 (m, 2H), 0.29-0.25 (m, 2H).

[0313]

[0314] Step 6-5: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0315] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (20.68 g, 0.056 mol) prepared in step 6-4 above (13.8 g, yield: 64.1%).

[0316] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.85-8.83 (dd, 1H), 8.48-8.47 (d, 1H), 7.83-7.80 (m, 1H), 7.60-7.57 (m, 1H), 7.52-7.46 (m, 1H), 7.41 (s, 1H), 7.21-7.15 (m, 2H), 7.06-7.02 (td, 1H), 3.55 (s, 2H), 2.31 (s, 3H), 1.42-1.37 (m, 1H), 0.45-0.42 (m, 2H), 0.11-0.06 (m, 2H).

[0317] [M+H] + : 386.34

[0318]

[0319] Example 7: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride

[0320]

[0321]

[0322] Hydrochloric acid (2.0 M diethyl ether solution) (1.43 mL, 2.854 mmol) was diluted in 50 mL of ethyl acetate, and 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (1.0 g, 2.594 mmol) prepared in step 6-5 above was dissolved in 6 mL of ethyl acetate and added dropwise. After stirring for 23 hours, the reaction mixture was filtered to obtain the title compound (0.82 g, yield: 75.2%).

[0323] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.13 (s, 2H), 8.88-8.86 (m, 1H), 8.50-8.49 (m, 1H), 7.86-7.84 (m, 2H), 7.61-7.58 (m, 1H), 7.55-7.49 (m, 1H), 7.22-7.15 (m, 2H), 7.02-6.98 (m, 1H), 4.07-4.04 (t, 2H), 2.63-2.60 (t, 3H), 1.51-1.45 (m, 1H), 0.50-0.47 (m, 2H), 0.06-0.05 (m, 2H)

[0324] [M+H] + : 386.34

[0325]

[0326] Example 8: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine 0.5 fumarate

[0327]

[0328]

[0329] Fumaric acid (23.5 g, 0.203 mol) was dissolved in 470 mL of methanol, and 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (130.6 g, 0.339 mol) prepared in step 6-5 above was dissolved in 2.35 L of ethyl acetate and added dropwise. After stirring for 13 hours, the reaction mixture was filtered to obtain the title compound (82.5 g, yield: 54.9%).

[0330] 1 H-NMR (400 MHz, DMSO-d 6): 8.85-8.83 (dd, 1H), 8.48-8.47 (d, 1H), 7.83-7.80 (m, 1H), 7.59-7.56 (m, 2H), 7.53-7.47 (m, 1H), 7.21-7.15 (m, 2H), 7.05-7.00 (td, 1H), 6.45 (s, 1H), 3.75 (s, 2H), 2.42 (s, 3H), 1.45-1.41 (m, 1H), 0.47-0.43 (m, 2H), 0.09-0.03 (m, 2H).

[0331] [M+H] + : 386.02

[0332]

[0333] Example 9: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine 2-hydroxypropane-1,2,3-tricarboxylate

[0334]

[0335]

[0336] Citric acid (0.15 g, 0.778 mmol) was dissolved in 0.7 mL of methanol, and 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (0.3 g, 0.778 mmol), prepared in step 6-5 above, was added dropwise thereto, dissolved in 3 mL of ethyl acetate. After stirring for 1 hour, the reaction mixture was filtered to obtain the title compound (0.1 g, yield: 22.0%).

[0337] 1 H-NMR (400 MHz, MeOD-d 4): 8.79-8.77 (m, 1H), 8.48-8.47 (d, 1H), 7.86-7.80 (m, 2H), 7.54-7.52 (m, 2H), 7.20-7.18 (m, 1H), 7.09-7.05 (m, 2H), 4.30 (s, 2H), 2.86-2.73 (m, 7H), 1.51-1.47 (m, 1H), 0.60-0.52 (m, 2H), 0.16-0.10 (m, 2H).

[0338] [M+H] + : 385.99

[0339]

[0340] Example 10: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine phosphate

[0341]

[0342]

[0343] 1-(4-Cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (200 mg, 0.519 mmol) prepared in the above step 6-5 was dissolved in 5 mL of ethyl acetate, and then phosphoric acid (64 mg, 0.519 mmol) diluted in 2 mL of ethyl acetate was added dropwise. After stirring for 21 hours, the reaction mixture was filtered to obtain the title compound (163 mg, yield: 64.9%).

[0344] 1 H-NMR (400 MHz, MeOD-d 4 ): 8.79-8.77 (dd, 1H), 8.49-8.48 (d, 1H), 7.89-7.86 (td, 1H), 7.81 (s, 1H), 7.55-7.48 (m, 2H), 7.22-7.17 (td, 1H), 7.08-7.03 (m, 2H), 4.19 (s, 2H), 2.77 (s, 3H), 1.49-1.48 (m, 1H), 0.57-0.55 (m, 2H), 0.15-0.12 (m, 2H).

[0345] [M+H] + : 386.34

[0346]

[0347] Example 11: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine 0.5 succinate

[0348]

[0349]

[0350] Succinic acid (0.31 g, 2.6 mmol) was dissolved in 4 mL of methanol, and 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (1.0 g, 2.6 mmol) prepared in step 6-5 above was added dropwise, dissolved in 16 mL of ethyl acetate. After stirring for 2 hours, the reaction mixture was filtered to obtain the title compound (0.4 g, yield: 30.8%).

[0351] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.86-8.85 (dd, 1H), 8.49-8.48 (d, 1H), 7.81-7.78 (m, 1H), 7.61-7.57 (qd, 1H), 7.56 (s, 1H), 7.53-7.48 (m, 1H), 7.22-7.15 (m, 2H), 7.05-7.01 (td, 1H), 3.78-3.74 (d, 2H), 2.46 (s, 3H), 1.46-1.39 (m, 1H), 0.47-0.43 (m, 2H), 0.10-0.03 (m, 2H).

[0352] [M+H] + : 386.36

[0353]

[0354] Example 12: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine 0.5 2,3-dihydroxysuccinate

[0355]

[0356]

[0357] Tartaric acid (0.39 g, 2.6 mmol) was dissolved in 8 mL of methanol, and 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (1.0 g, 2.6 mmol) prepared in step 6-5 above was added dropwise, dissolved in 32 mL of ethyl acetate. After stirring for 20 hours, the reaction mixture was filtered to obtain the title compound (0.7 g, yield: 50.7%).

[0358] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.87-8.85 (dd, 1H), 8.49-8.48 (d, 1H), 7.83-7.80 (m, 1H), 7.69 (s, 1H), 7.61-7.58 (m, 1H), 7.55-7.49 (m, 1H), 7.22-7.15 (m, 2H), 7.03-6.99 (m, 1H), 3.96 (s, 2H), 3.91 (s, 3H), 2.57 (s, 3H), 1.49-1.42 (m, 1H), 0.52-0.43 (m, 2H), 0.10-0.00 (m, 2H).

[0359] [M+H] + : 386.36

[0360]

[0361] Example 13: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0362]

[0363]

[0364] Step 13-1: Preparation of methyl 4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-1H-pyrrole-3-carboxylate

[0365] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (2.24 g, 0.009 mol) and 6-methylpyridine-3-sulfonyl chloride (2.48 g, 0.013 mol) prepared in step 6-1 above (3.19 g, yield: 89.1%).

[0366] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.35-8.34 (d, 1H), 8.09 (s, 1H), 7.82-7.80 (dd, 1H), 7.57-7.51 (m, 1H), 7.46-7.44 (d, 1H), 7.22-7.15 (m, 2H), 7.08-7.04 (td, 1H), 3.77 (s, 3H), 2.55 (s, 3H), 1.77-1.72 (m, 1H), 0.49-0.45 (m, 2H), 0.10-0.06 (m, 2H).

[0367]

[0368] Step 13-2: Preparation of (4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methanol

[0369] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-1H-pyrrole-3-carboxylate (3.19 g, 0.008 mol) prepared in step 13-1 above (2.22 g, yield: 74.0%).

[0370] 1 H-NMR (400 MHz, DMSO-d 6): 8.35-8.34 (d, 1H), 7.71-7.68 (dd, 1H), 7.52-7.47 (m, 1H), 7.45-7.42 (d, 1H), 7.36 (s, 1H), 7.22-7.16 (m, 2H), 7.08-7.04 (td, 1H), 5.00-4.97 (t, 1H), 4.38-4.37 (d, 2H), 2.53 (s, 3H), 1.39-1.35 (m, 1H), 0.45-0.41 (m, 2H), 0.18-0.13 (m, 2H).

[0371]

[0372] Step 13-3: Preparation of 4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-1H-pyrrole-3-carbaldehyde

[0373] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methanol (2.22 g, 0.006 mol) prepared in step 13-2 above (1.72 g, yield: 78.1%).

[0374] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.89 (s, 1H), 8.45 (s, 1H), 8.37-8.36 (d, 1H), 7.80-7.78 (dd, 1H), 7.58-7.52 (m, 1H), 7.48-7.46 (d, 1H), 7.23-7.16 (d, 2H), 7.10-7.05 (td, 1H), 2.55 (s, 3H), 1.69-1.62 (m, 1H), 0.54-0.49 (m, 2H), 0.29-0.25 (m, 2H).

[0375]

[0376] Step 13-4: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0377] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-1H-pyrrole-3-carbaldehyde (1.72 g, 0.005 mol) prepared in step 13-3 above (1.39 g, yield: 78.1%).

[0378] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.35-8.34 (d, 1H), 7.71-7.69 (dd, 1H), 7.51-7.49 (m, 1H), 7.45-7.42 (d, 1H), 7.38 (s, 1H), 7.22-7.18 (m, 2H), 7.07-7.03 (td, 1H), 3.54-3.54 (d, 2H), 2.54 (s, 3H), 2.32 (s, 3H), 1.43-1.36 (m, 1H), 0.46-0.41 (m, 2H), 0.12-0.07 (m, 2H).

[0379] [M+H] + : 400.34

[0380]

[0381] Example 14: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0382]

[0383]

[0384] Step 14-1: Preparation of methyl 4-cyclopropyl-5-(2-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrrole-3-carboxylate

[0385] The title compound was prepared in the same manner as in step 6-2 using methyl 4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (1.30 g, 0.005 mol) and 3-(trifluoromethyl)benzenesulfonyl chloride (1.77 g, 0.007 mol) prepared in step 6-1 (2.2 g, yield: 98.7%).

[0386] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.16-8.14 (m, 2H), 7.95-7.93 (m, 1H), 7.84-7.80 (m, 1H), 7.56-7.50 (m, 2H), 7.19-7.02 (m, 3H), 3.78 (s, 3H), 1.76-1.72 (m, 1H), 0.48-0.45 (m, 2H), 0.10-0.06 (m, 2H).

[0387]

[0388] Step 14-2: Preparation of (4-cyclopropyl-5-(2-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methanol

[0389] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrrole-3-carboxylate (2.1 g, 0.005 mol) prepared in step 14-1 above (1.91 g, yield: 96.5%).

[0390] 1 H-NMR (400 MHz, DMSO-d 6): 8.12-8.08 (dd, 1H), 7.93-7.85 (m, 2H), 7.51-7.49 (m, 1H), 7.44-7.41 (m, 2H), 7.18-7.15 (m, 2H), 7.06-7.04 (m, 1H), 5.06-4.98 (t, 1H), 4.44-4.37 (m, 2H), 1.38-1.34 (m, 1H), 0.44-0.42 (m, 2H), 0.17-0.15 (m, 2H).

[0391]

[0392] Step 14-3: Preparation of 4-cyclopropyl-5-(2-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde

[0393] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(2-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methanol (1.84 g, 0.004 mol) prepared in step 14-2 above (1.37 g, yield: 74.5%).

[0394] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.91 (s, 1H), 8.52 (s, 1H), 8.19-8.15 (m, 1H), 7.94-7.83 (m, 2H), 7.56-7.53 (m, 2H), 7.19-7.06 (m, 1H), 1.68-1.64 (m, 1H), 0.53-0.50 (m, 2H), 0.28-0.26 (m, 2H).

[0395]

[0396] Step 14-4: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0397] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde (0.91 g, 0.002 mol) prepared in step 14-3 above (0.85 g, yield: 90.4%).

[0398] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.12-8.08 (m, 1H), 7.85-7.79 (m, 2H), 7.53-7.42 (m, 3H), 7.20-7.13 (m, 2H), 7.05-7.01 (m, 1H), 3.54 (s, 2H), 2.29 (s, 3H), 1.41-1.36 (m, 1H), 0.47-0.39 (m, 2H), 0.09-0.06 (m, 2H).

[0399] [M+H] + : 453.02

[0400]

[0401] Example 15: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0402]

[0403]

[0404] Step 15-1: Preparation of (4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methanol

[0405] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (14.0 g, 0.051 mol) prepared in step 6-1 above (10.5 g, yield: 88.8%).

[0406] 1 H-NMR (400 MHz, DMSO-d 6): 11.94 (s, 1H), 7.75-7.71 (m, 2H), 7.52-7.48 (td, 1H), 7.29-7.25 (t, 1H), 6.41 (s, 1H), 5.27 (s, 1H), 4.51 (s, 2H), 2.35-2.19 (m, 1H), 1.28-1.09 (m, 2H), 1.00-0.84 (m, 2H).

[0407]

[0408] Step 15-2: Preparation of 4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde

[0409] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methanol (10.5 g, 0.045 mol) prepared in step 15-1 above (3.70 g, yield: 35.5%).

[0410] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.76 (s, 1H), 9.80 (s, 1H), 7.59 (s, 1H), 7.49-7.39 (m, 2H), 7.31-7.24 (m, 2H), 1.85-1.79 (m, 1H), 0.68-0.63 (m, 2H), 0.29-0.25 (m, 2H).

[0411]

[0412] Step 15-3: Preparation of 4-cyclopropyl-5-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde

[0413] The title compound was prepared in the same manner as in step 1-5 using 4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (1.0 g, 0.004 mol) and 3-fluorophenylsulfonyl chloride (1.70 g, 0.008 mol) prepared in step 15-2 above (1.2 g, yield: 85.0%).

[0414] 1H-NMR (400 MHz, DMSO-d 6 ): 9.73 (s, 1H), 7.81-7.45 (m, 7H), 7.29-7.26 (m, 1H), 7.06 (s, 1H), 2.24-2.21 (m, 1H), 1.25-0.87 (m, 4H).

[0415]

[0416] Step 15-4: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0417] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde (1.2 g, 0.003 mol) prepared in step 15-3 above (0.70 g, yield: 56.0%).

[0418] 1 H-NMR (400 MHz, DMSO-d 6 ): 7.63-7.55 (m, 2H), 7.51-7.46 (m, 1H), 7.37 (s, 1H), 7.27-7.24 (m, 1H), 7.24-7.13 (m, 3H), 7.07-7.01 (td, 1H), 3.53-3.52 (d, 2H), 2.30 (s, 3H), 1.43-1.36 (m, 1H), 0.46-0.38 (m, 2H), 0.12-0.05 (m, 2H).

[0419] [M+H] + : 402.95

[0420]

[0421] Example 16: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0422]

[0423]

[0424] Step 16-1: Preparation of 4-cyclopropyl-5-(2-fluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde

[0425] The title compound was prepared in the same manner as in step 1-5 using 4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (1.0 g, 0.004 mol) and 3-methoxyphenylsulfonyl chloride (1.35 g, 0.007 mol) prepared in step 15-2 above (1.6 g, yield: 92.0%).

[0426] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.89 (s, 1H), 8.45-8.44 (d, 1H), 7.55-7.53 (m, 1H), 7.51-7.47 (m, 1H), 7.32-7.31 (dd, 1H), 7.20-7.18 (m, 2H), 7.05-7.04 (m, 2H), 6.85-6.84 (t, 1H), 3.73 (s, 3H), 1.68-1.64 (m, 1H), 0.54-0.49 (m, 2H), 0.29-0.27 (m, 2H).

[0427]

[0428] Step 16-2: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0429] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-fluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde (1.39 g, 0.003 mol) prepared in step 16-1 above (1.33 g, yield: 92.4%).

[0430] 1 H-NMR (400 MHz, DMSO-d 6): 7.49-7342 (m, 2H), 7.35 (s, 1H), 7.25-7.24 (m, 1H), 7.20-7.17 (m, 2H), 7.04-7.01 (m, 2H), 6.79-6.78 (t, 1H), 3.72 (s, 3H), 3.53-3.52 (d, 2H), 2.30 (s, 3H), 1.42-1.37 (m, 1H), 0.46-0.40 (m, 2H), 0.11-0.07 (m, 2H).

[0431] [M+H] + : 415.35

[0432]

[0433] Example 17: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0434]

[0435]

[0436] Step 17-1: Preparation of 4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carbaldehyde

[0437] The title compound was prepared in the same manner as in step 1-5 using 4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (0.5 g, 0.0022 mol) and 6-methoxypyridine-3-sulfonyl chloride (0.50 g, 0.0024 mol) prepared in step 15-2 above (0.78 g, yield: 89.7%).

[0438] 1 H-NMR (400 MHz, DMSO-d 6): 9.90 (s, 1H), 8.42 (s, 1H), 8.10 (s, 1H), 7.77-7.74 (dd, 1H), 7.56-7.54 (m, 1H), 7.23-7.19 (m, 2H), 7.11-7.10 (m, 1H), 6.98-6.96 (d, 1H), 3.93 (s, 3H), 1.69-1.65 (m, 1H), 0.54-0.51 (m, 2H), 0.30-0.28 (m, 2H).

[0439]

[0440] Step 17-2: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0441] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carbaldehyde (1.1 g, 0.003 mol) prepared in step 17-1 above (0.59 g, yield: 52.0%).

[0442] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.08-8.07 (d, 1H), 7.66-7.63 (dd, 1H), 7.52-7.46 (m, 1H), 7.39 (s, 1H), 7.22-7.16 (m, 2H), 7.08-7.04 (td, 1H), 6.95-6.92 (d, 1H), 3.90 (s, 3H), 3.59 (s, 2H), 2.35 (s, 3H), 1.44-1.37 (m, 1H), 0.47-0.39 (m, 2H), 0.13-0.04 (m, 2H).

[0443] [M+H] + : 415.99

[0444]

[0445] Example 18: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0446]

[0447]

[0448] Step 18-1: Preparation of 4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0449] The title compound was prepared in the same manner as in step 1-5 using 4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (0.7 g, 0.003 mol) and pyridine-2-sulfonyl chloride (0.81 g, 0.005 mol) prepared in step 15-2 above (0.74 g, yield: 65.5%).

[0450] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.94 (s, 1H), 8.75-8.73 (d, 1H), 8.41-8.40 (d, 1H), 8.04-7.99 (td, 1H), 7.78-7.76 (m, 1H), 7.51-7.45 (m, 2H), 7.13-7.07 (m, 2H), 6.91-6.87 (td, 1H), 1.71-1.67 (m, 1H), 0.54-0.50 (m, 2H), 0.30-0.27 (m, 2H).

[0451]

[0452] Step 18-2: Preparation of 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0453] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.7 g, 0.002 mol) prepared in step 18-1 above (0.28 g, yield: 38.4%).

[0454] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.69-8.67 (m, 1H), 8.01-7.97 (td, 1H), 7.71-7.68 (qd, 1H), 7.44-7.40 (m, 2H), 7.33 (s, 1H), 7.11-7.07 (m, 2H), 6.95-6.91 (td, 1H), 3.58 (s, 2H), 2.34 (s, 3H), 1.43-1.39 (m, 1H), 0.46-0.41 (m, 2H), 0.13-0.09 (m, 2H).

[0455] [M+H] + : 386.34

[0456]

[0457] Example 19: Preparation of 1-(1-((4-(1H-pyrazol-1-yl)phenyl)sulfonyl)-4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0458]

[0459]

[0460] Step 19-1: Preparation of tert-butyl ((4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate

[0461] 4-Cyclopropyl-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (2.5 g, 0.011 mol) prepared in the above step 15-2 was dissolved in 25 mL of methylamine (9.8 M methanol solution) and stirred for 40 minutes. Then, sodium borohydride (0.83 g, 0.022 mol) was added and stirred for 2 hours. Purified water was added to the reaction mixture, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was dissolved in 40 mL of dichloromethane, triethylamine (2.2 g, 0.022 mol) was added, and di-tert-butyl dicarbonate (3.57 g, 0.016 mol) was slowly added. After stirring at room temperature for 2 hours, purified water was added, and extraction with dichloromethane was performed. The obtained extract was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain the title compound (3.7 g, yield: 98.7%).

[0462] 1 H-NMR (400 MHz, DMSO-d 6 ): 10.71 (s, 1H), 7.48-7.45 (t, 1H), 7.34-7.29 (m, 1H), 7.25-7.20 (q, 2H), 6.63 (s, 1H), 4.32 (s, 2H), 2.76 (s, 3H), 1.62 (s, 1H), 1.42 (s, 9H), 0.62 (m, 2H), 0.04-0.01 (m, 2H).

[0463]

[0464] Step 19-2: Preparation of tert-butyl ((1-((4-(1H-pyrazol-1-yl)phenyl)sulfonyl)-4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate

[0465] The title compound was prepared in the same manner as in Step 1-5 using tert-butyl ((4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (0.8 g, 0.002 mol) and 4-(1H-pyrazol-1-yl)benzenesulfonyl chloride (0.84 g, 0.003 mol) prepared in Step 19-1 above (0.59 g, yield: 46.1%).

[0466] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.65-8.62 (dd, 1H), 8.00-7.98 (d, 2H), 7.84-7.81 (m, 1H), 7.51-7.46 (m, 3H), 7.32 (s, 1H), 7.20-7.18 (m, 2H), 7.09-7.05 (m, 1H), 6.63-6.59 (m, 1H), 4.31 (s, 2H), 2.77 (s, 3H), 1.39 (s, 9H) 1.24-1.22 (m, 1H), 0.48-0.39 (m, 2H), 0.04-0.00 (m, 2H).

[0467]

[0468] Step 19-3: Preparation of 1-(1-((4-(1H-pyrazol-1-yl)phenyl)sulfonyl)-4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0469] Tert-butyl ((1-((4-(1H-pyrazol-1-yl)phenyl)sulfonyl)-4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (0.59 g, 0.001 mol) prepared in the above step 19-2 was dissolved in 12 mL of dichloromethane, 1 mL of hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. After adding a saturated aqueous sodium bicarbonate solution, the mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered, concentrated, and then purified by silica gel column chromatography (dichloromethane: methanol = 9:1) to obtain the title compound (0.17 g, yield: 35.4%).

[0470] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.64-8.63 (d, 1H), 8.02-7.97 (td, 2H), 7.84-7.83 (d, 1H), 7.50-7.47 (m, 3H), 7.39 (s, 1H), 7.20-7.18 (m, 2H), 7.08-7.04 (td, 1H), 6.27-6.62 (m, 1H), 3.56 (s, 2H), 1.42-1.36 (m, 1H), 0.46-0.41 (m, 1H), 0.11-0.08 (m, 2H).

[0471] [M+H] + : 451.43

[0472]

[0473] Example 20: Preparation of 1-(4-cyclopropyl-5-(4-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0474]

[0475]

[0476] Step 20-1: Preparation of methyl 4-cyclopropyl-5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate

[0477] Methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.016 mol) prepared in the above step 1-3 was dissolved in 72 mL of toluene, and then 4-fluorophenylboronic acid (4.48 g, 0.032 mol), 8 mL of purified water, sodium carbonate (5.09 g, 0.048 mol), and Pd(PPh3)4 (0.92 g, 0.0008 mol) were sequentially added and stirred under reflux for 2 hours. After cooling the reaction mixture to room temperature, purified water was added, and the mixture was extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate: chloroform = 1:20) to obtain the title compound (3.01 g, yield: 72.5%).

[0478] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.55 (s, 1H), 7.58-7.54 (m, 2H), 7.38-7.37 (d, 1H), 7.27-7.22 (m, 2H), 3.69 (s, 3H), 1.89-1.82 (m, 1H), 0.76-0.73 (m, 2H), 0.08-0.05 (m, 2H).

[0479]

[0480] Step 20-2: Preparation of methyl 4-cyclopropyl-5-(4-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carboxylate

[0481] The title compound was prepared in the same manner as in step 6-2 using methyl 4-cyclopropyl-5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate (1.5 g, 0.006 mol) and 3-fluorophenylsulfonyl chloride (1.69 g, 0.009 mol) prepared in step 20-1 above (2.30 g, yield: 95.4%).

[0482] 1 H-NMR (400 MHz, DMSO-d 6): 7.96 (s, 1H), 7.89-7.78 (m, 3H), 7.69-7.68 (m, 1H), 7.59-7.50 (m, 2H), 7.34-7.30 (m, 2H), 3.90 (s, 3H), 2.25-2.21 (m, 1H), 1.20-1.17 (m, 2H), 0.96-0.90 (m, 2H).

[0483]

[0484] Step 20-3: Preparation of (4-cyclopropyl-5-(4-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)methanol

[0485] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(4-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carboxylate (2.30 g, 0.006 mol) prepared in step 20-2 above (2.00 g, yield: 93.5%).

[0486] 1 H-NMR (400 MHz, DMSO-d 6 ): 7.89-7.77 (m, 3H), 7.69-7.67 (m, 1H), 7.59-7.50 (m, 2H), 7.33-7.30 (m, 2H), 6.73 (s, 1H), 5.35-5.32 (t, 1H), 4.54-4.50 (m, 2H), 2.37-2.19 (m, 1H), 1.23-0.97 (m, 4H).

[0487]

[0488] Step 20-4: Preparation of 4-cyclopropyl-5-(4-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde

[0489] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(4-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)methanol (2.00 g, 0.005 mol) prepared in step 20-3 above (1.49 g, yield: 75.3%).

[0490] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.81 (s, 1H), 7.90-7.77 (m, 3H), 7.70-7.68 (m, 1H), 7.58-7.50 (m, 2H), 7.33-7.30 (m, 2H), 7.08 (s, 1H), 2.32-2.17 (m, 1H), 1.32-1.27 (m, 2H), 1.17-0.92 (m, 2H).

[0491]

[0492] Step 20-5: Preparation of 1-(4-cyclopropyl-5-(4-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0493] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(4-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde (1.49 g, 0.004 mol) prepared in step 20-4 above (0.83 g, yield: 53.5%).

[0494] 1 H-NMR (400 MHz, DMSO-d 6 ): 7.61-7.54 (m, 2H), 7.85-7.79 (m, 2H), 7.32 (s, 1H), 7.22-7.05 (m, 6H), 3.52 (s, 2H), 2.30 (s, 3H), 1.44-1.40 (m, 1H), 0.47-0.42 (m, 2H), 0.07-0.03 (m, 2H).

[0495] [M+H] + : 403.98

[0496]

[0497] Example 21: Preparation of 1-(5-(4-(1H-pyrrol-1-yl)phenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl-N-methylmethanamine

[0498]

[0499]

[0500] Step 21-1: Preparation of methyl 5-(4-aminophenyl)-4-cyclopropyl-1H-pyrrole-3-carboxylate

[0501] Methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.061 mol) prepared in the above step 1-3 was dissolved in 200 mL of 1,4-dioxane, and then 4-aminophenylboronic acid pinacol ester (16.0 g, 0.073 mol), 100 mL of purified water, sodium carbonate (16.0 g, 0.153 mol), and Pd(PPh3)4 (7.0 g, 0.006 mol) were sequentially added and stirred under reflux for 20 hours. After cooling the reaction mixture to room temperature, purified water was added, and the mixture was extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to obtain the title compound (12.5 g, yield: 79.3%).

[0502] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.16 (s, 1H), 7.23-7.22 (d, 1H), 7.18-7.16 (m, 2H), 6.57-6.54 (m, 1H), 6.46-6.38 (m, 1H), 4.34 (s, 2H), 3.67 (s, 3H), 1.82-1.78 (m, 1H), 0.72-0.66 (m, 2H), 0.12-0.08 (m, 2H).

[0503]

[0504] Step 21-2: Preparation of methyl 5-(4-(1H-pyrrole-1-yl)phenyl)-4-cyclopropyl-1H-pyrrole-3-carboxylate

[0505] Methyl 5-(4-aminophenyl)-4-cyclopropyl-1H-pyrrole-3-carboxylate (12.5 g, 0.049 mol) prepared in the above step 21-1 was dissolved in 100 mL of acetonitrile and 100 mL of purified water, 2,5-dimethoxytetrahydrofuran (8.2 mL, 0.063 mol) and copper(II) chloride (0.66 g, 0.005 mol) were added, and the mixture was stirred under reflux for 15 hours. After cooling the reaction mixture to room temperature, purified water was added, and the mixture was extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to obtain the title compound (4.5 g, yield: 30.2%).

[0506] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.56 (s, 1H), 7.62 (s, 4H), 7.42-7.41 (t, 2H), 7.83 (s, 1H), 6.27-6.26 (t, 2H), 3.70 (s, 3H), 1.93-1.86 (m, 1H), 0.81-0.76 (m, 2H), 0.14-0.10 (m, 2H).

[0507]

[0508] Step 21-3: Preparation of methyl 5-(4-(1H-pyrrol-1-yl)phenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

[0509] The title compound was prepared in the same manner as in step 1-5 using methyl 5-(4-(1H-pyrrole-1-yl)phenyl)-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.57 g, 0.002 mol) prepared in step 21-2 and pyridine-3-sulfonyl chloride (0.3 mL, 0.003 mol) (0.62 g, yield: 72.1%).

[0510] 1 H-NMR (400 MHz, DMSO-d 6): 8.86-8.84 (dd, 1H), 8.49-8.48 (m, 1H), 8.05 (s, 1H), 7.91-7.88 (m, 1H), 7.58-7.53 (m, 3H), 7.48-7.47 (m, 2H), 7.06-7.03 (m, 2H), 6.31-6.29 (t, 2H), 3.78 (s, 3H), 1.80-1.73 (m, 1H), 0.50-0.45 (m, 2H), 0.11-0.07 (m, 2H).

[0511]

[0512] Step 21-4: Preparation of 5-(4-(1H-pyrrol-1-yl)phenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0513] Methyl 5-(4-(1H-pyrrol-1-yl)phenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (0.70 g, 0.002 mol) prepared in the above step 21-3 was dissolved in 50 mL of tetrahydrofuran, cooled to -78°C, and diisobutylaluminum hydride (1.0 M toluene solution) (12 mL, 0.012 mol) was added dropwise. After stirring in a cooled state for 3 hours, the temperature was increased to 0°C, and purified water, 1 N aqueous sodium hydroxide solution, and diethyl ether were added in sequence, followed by stirring for 15 minutes. Anhydrous magnesium sulfate and diatomaceous earth were added, stirred for 15 minutes more, filtered, and the filtrate was concentrated. The concentrate was dissolved in 30 mL of dichloromethane, manganese dioxide (1.36 g, 0.015 mol) was added, and the mixture was stirred for 21 hours. The reaction mixture was filtered, the filtrate was concentrated, and then purified by column chromatography (ethyl acetate: n-hexane = 1:10) to obtain the title compound (0.086 g, yield: 8.8%).

[0514] 1 H-NMR (400 MHz, DMSO-d 6): 9.92 (s, 1H), 8.87-8.86 (dd, 1H), 8.51-8.50 (d, 1H), 8.42 (s, 1H), 7.90-7.87 (m, 1H), 7.60-7.58 (m, 1H), 7.57-7.54 (m, 2H), 7.48-7.47 (t, 2H), 7.07-7.04 (m, 2H), 6.31-6.30 (t, 2H), 1.73-1.66 (m, 1H), 0.55-0.50 (m, 2H), 0.31-0.28 (m, 2H).

[0515]

[0516] Step 21-5: Preparation of 1-(5-(4-(1H-pyrrol-1-yl)phenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl-N-methylmethanamine

[0517] The title compound was prepared in the same manner as in step 1-8 using 5-(4-(1H-pyrrol-1-yl)phenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.085 g, 0.20 mmol) prepared in step 21-4 above (25 mg, yield: 28.4%).

[0518] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.83-8.81 (dd, 1H), 8.46-8.45 (d, 1H), 7.79-7.77 (d, 1H), 7.58-7.54 (m, 3H), 7.48-7.47 (m, 2H), 7.34 (s, 1H), 7.11-7.09 (d, 2H), 6.30-6.29 (s, 2H), 3.53 (s, 2H), 2.30-2.28 (d, 3H), 1.47-1.43 (m, 1H), 0.85-0.82 (m, 2H), 0.49-0.44 (m, 2H).

[0519] [M+H] + : 433.04

[0520]

[0521] Example 22: Preparation of 1-(4-cyclopropyl-5-(2-fluoro-4-(1H-pyrrol-1-yl)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0522]

[0523]

[0524] Step 22-1: Preparation of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0525] 4-Bromo-3-fluorophenylamine (30 g, 0.158 mol) was dissolved in 700 mL of 1,4-dioxane, and bis(pinacolato)diborane (60 g, 0.237 mol), potassium acetate (31 g, 0.316 mol), and Pd(dppf)Cl2 (13 g, 0.016 mol) were sequentially added, and the mixture was refluxed and stirred for 20 hours. After cooling the reaction mixture to room temperature, purified water was added, and the mixture was extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:5) to obtain the title compound (16 g, yield: 42.7%).

[0526] 1 H-NMR (400 MHz, DMSO-d 6 ): 7.61-7.57 (m, 1H), 6.93-6.89 (m, 1H), 6.61-6.56 (m, 1H), 5.19 (s, 2H), 1.25 (s, 12H).

[0527]

[0528] Step 22-2: Preparation of methyl 5-(4-amino-2-fluorophenyl)-4-cyclopropyl-1H-pyrrole-3-carboxylate

[0529] Methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.019 mol) prepared in the above step 1-3 was dissolved in 60 mL of 1,4-dioxane, and then 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.5 g, 0.023 mol) prepared in the above step 22-1, 30 mL of purified water, sodium carbonate (5.1 g, 0.048 mol), and Pd(PPh3)4 (2.24 g, 0.002 mol) were sequentially added and stirred under reflux for 20 hours. After cooling the reaction mass to room temperature, purified water was added, and extraction was performed with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain the title compound (4.6 g, yield: 86.6%).

[0530] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.15 (s, 1H), 7.27-7.26 (d, 1H), 7.02-6.98 (t, 1H), 6.40-6.32 (m, 2H), 5.49 (s, 2H), 3.67 (s, 3H), 7.11-7.09 (d, 2H), 6.30-6.29 (s, 2H), 1.97-1.77 (m, 1H), 0.59-0.54 (m, 2H), 0.13-0.09 (m, 2H).

[0531]

[0532] Step 22-3: Preparation of methyl 4-cyclopropyl-5-(2-fluoro-4-(1H-pyrrol-1-yl)phenyl)-1H-pyrrole-3-carboxylate

[0533] The title compound was prepared in the same manner as in step 21-2 using methyl 5-(4-amino-2-fluorophenyl)-4-cyclopropyl-1H-pyrrole-3-carboxylate (4.6 g, 0.017 mol) prepared in step 22-2 (2.2 g, yield: 40.4%).

[0534] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.50 (s, 1H), 7.65-7.62 (dd, 1H), 7.53-7.46 (m, 4H), 7.42-7.41 (d, 1H), 5.49 (s, 2H), 3.70 (s, 3H), 1.88-1.83 (m, 1H), 0.66-0.61 (m, 2H), 0.11-0.08 (m, 2H).

[0535]

[0536] Step 22-4: Preparation of (4-cyclopropyl-5-(2-fluoro-4-(1H-pyrrol-1-yl)phenyl)-1H-pyrrol-3-yl)methanol

[0537] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2-fluoro-4-(1H-pyrrol-1-yl)phenyl)-1H-pyrrole-3-carboxylate (2.2 g, 0.007 mol) prepared in step 22-3 above (1.4 g, yield: 69.7%).

[0538] 1 H-NMR (400 MHz, DMSO-d 6 ): 10.62 (s, 1H), 7.59-7.45 (m, 5H), 6.68-6.67 (d, 1H), 6.28-6.26 (m, 2H), 4.44-4.40 (m, 3H), 1.70-1.63 (m, 1H), 0.63-0.59 (m, 2H), 0.22-0.18 (m, 2H).

[0539]

[0540] Step 22-5: Preparation of 4-cyclopropyl-5-(2-fluoro-4-(1H-pyrrol-1-yl)phenyl)-1H-pyrrole-3-carbaldehyde

[0541] (4-Cyclopropyl-5-(2-fluoro-4-(1H-pyrrol-1-yl)phenyl)-1H-pyrrol-3-yl)methanol (1.4 g, 0.005 mol) prepared in the above step 22-4 was dissolved in 24 mL of dichloromethane, manganese dioxide (4.1 g, 0.047 mol) was added, and the mixture was stirred for 20 hours. The reaction mixture was filtered, and the filtrate was concentrated and purified by column chromatography (ethyl acetate:n-hexane = 1:5) to obtain the title compound (0.26 g, yield: 18.7%).

[0542] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.78 (s, 1H), 9.81 (s, 1H), 7.67-7.50 (m, 5H), 6.29-6.28 (t, 2H), 5.74 (s, 1H), 1.86-1.82 (m, 1H), 0.71-0.66 (m, 2H), 0.32-0.28 (m, 2H).

[0543]

[0544] Step 22-6: Preparation of 4-cyclopropyl-5-(2-fluoro-4-(1H-pyrrol-1-yl)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0545] The title compound was prepared in the same manner as in step 1-5 using 4-cyclopropyl-5-(2-fluoro-4-(1H-pyrrol-1-yl)phenyl)-1H-pyrrole-3-carbaldehyde (0.26 g, 0.894 mmol) prepared in step 22-5 and pyridine-3-sulfonyl chloride (0.12 mL, 1.340 mmol) (0.27 g, yield: 68.4%).

[0546] 1 H-NMR (400 MHz, DMSO-d 6): 9.91 (s, 1H), 8.92-8.90 (dd, 1H), 8.62-8.61 (d, 1H), 8.49 (s, 1H), 7.99-7.96 (m, 1H), 7.65-7.62 (m, 1H), 7.58-7.55 (m, 3H), 7.50-7.48 (dd, 1H), 7.15-7.11 (t, 1H), 6.32-6.31 (t, 2H), 1.73-1.66 (m, 1H), 0.58-0.53 (m, 2H), 0.34-0.30 (m, 2H).

[0547]

[0548] Step 22-7: Preparation of 1-(4-cyclopropyl-5-(2-fluoro-4-(1H-pyrrol-1-yl)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0549] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-fluoro-4-(1H-pyrrol-1-yl)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.27 g, 0.20 mmol) prepared in step 22-6 above (0.15 g, yield: 55.6%).

[0550] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.86-8.84 (dd, 1H), 8.55-8.54 (d, 1H), 7.88-7.85 (m, 1H), 7.61-7.59 (m, 1H), 7.58-7.54 (m, 2H), 7.49-7.44 (m, 3H), 7.11-7.07 (t, 1H), 6.31-6.30 (t, 2H), 3.58 (s, 2H), 2.33 (s, 3H), 1.43-1.41 (m, 1H), 0.49-0.47 (m, 2H), 0.15-0.11 (m, 2H).

[0551] [M+H] + : 451.07

[0552]

[0553] Example 23: Preparation of 1-(4-cyclopropyl-5-(4-(cyclopropylmethoxy)-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0554]

[0555]

[0556] Step 23-1: Preparation of (4-(cyclopropylmethoxy)-2-fluorophenyl)boronic acid

[0557] 2-Fluoro-4-hydroxyphenylboronic acid (4 g, 0.026 mol) was dissolved in 50 mL of N,N-dimethylformamide, potassium carbonate (7.09 g, 0.051 mol) and (bromomethyl)cyclopropane (4.16 g, 0.031 mol) were added, and the mixture was stirred at 60°C for 2 hours and 30 minutes. The reaction mixture was cooled to 0°C, purified water was added, and extracted with ethyl acetate. The obtained extract was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2) to obtain the title compound (3.88 g, yield: 72.0%).

[0558] 1 H-NMR (400 MHz, DMSO-d 6 ): 7.50-7.46 (t, 1H), 6.72-6.62 (m, 2H), 3.82-3.80 (d, 2H), 3.32 (s, 2H), 1.22-1.15 (m, 1H), 0.57-0.52 (m, 2H), 0.31-0.28 (m, 2H).

[0559]

[0560] Step 23-2: Preparation of methyl 4-cyclopropyl-5-(4-(cyclopropylmethoxy)-2-fluorophenyl)-1H-pyrrole-3-carboxylate

[0561] The title compound was prepared in the same manner as in step 22-2 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.012 mol) prepared in step 1-3 above and (4-(cyclopropylmethoxy)-2-fluorophenyl)boronic acid (3.81 g, 0.018 mol) prepared in step 23-1 above (2.06 g, yield: 52.2%).

[0562] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.35 (s, 1H), 7.35-7.34 (d, 1H), 7.31-7.27 (t, 1H), 6.88-6.79 (qd, 2H), 3.86-3.84 (d, 2H), 3.68 (s, 3H), 1.85-1.78 (m, 1H), 1.25-1.18 (m, 1H), 0.60-0.54 (m, 4H), 0.34-0.30 (m, 2H), 0.08-0.05 (m, 2H).

[0563]

[0564] Step 23-3: Preparation of methyl 4-cyclopropyl-5-(4-(cyclopropylmethoxy)-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

[0565] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(4-(cyclopropylmethoxy)-2-fluorophenyl)-1H-pyrrole-3-carboxylate (3.0 g, 0.009 mol) and pyridine-3-sulfonyl chloride (2.43 g, 0.014 mol) prepared in step 23-2 above (4.19 g, yield: 97.7%).

[0566] 1 H-NMR (400 MHz, DMSO-d 6): 8.89-8.87 (dd, 1H), 8.54-8.53 (d, 1H), 8.08 (s, 1H), 7.94-7.91 (m, 1H), 7.61-7.58 (qd, 1H), 6.92-6.88 (m, 1H), 6.75 (s, 1H), 6.73-6.71 (m, 1H), 3.88-3.86 (d, 2H), 3.78 (s, 3H), 1.79-1.72 (m, 1H), 1.26-1.21 (m, 1H), 0.61-0.57 (m, 2H), 0.51-0.46 (m, 2H), 0.37-0.33 (m, 2H), 0.13-0.09 (m, 2H).

[0567]

[0568] Step 23-4: Preparation of (4-cyclopropyl-5-(4-(cyclopropylmethoxy)-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol

[0569] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(4-(cyclopropylmethoxy)-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (4.0 g, 0.009 mol) prepared in step 23-3 above (3.14 g, yield: 83.5%).

[0570] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.85-8.83 (dd, 1H), 8.50-8.49 (d, 1H), 7.83-7.80 (m, 1H), 7.60-7.57 (qd, 1H), 7.36 (s, 1H), 6.92-6.87 (t, 1H), 6.77-6.73 (m, 2H), 4.99-4.96 (t, 1H), 4.39-4.35 (dd, 2H), 3.87-3.85 (d, 2H), 1.39-1.32 (m, 1H), 1.27-1.20 (m, 1H), 0.61-0.56 (m, 2H), 0.49-0.40 (m, 2H), 0.36-0.32 (m, 2H), 0.21-0.13 (m, 2H).

[0571]

[0572] Step 23-5: Preparation of 4-cyclopropyl-5-(4-(cyclopropylmethoxy)-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0573] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(4-(cyclopropylmethoxy)-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol (3.0 g, 0.007 mol) prepared in step 23-4 above (2.05 g, yield: 68.6%).

[0574] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.89 (s, 1H), 8.90-8.89 (dd, 1H), 8.56-8.55 (d, 1H), 8.44 (s, 1H), 7.92-7.89 (m, 1H), 7.63-7.60 (qd, 1H), 6.93-6.89 (t, 1H), 6.76-6.73 (m, 2H), 3.88-3.87 (d, 2H), 1.71-1.64 (m, 1H), 1.28-1.21 (m, 1H), 0.61-0.50 (m, 4H), 0.37-0.27 (m, 4H).

[0575]

[0576] Step 23-6: Preparation of 1-(4-cyclopropyl-5-(4-(cyclopropylmethoxy)-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0577] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(4-(cyclopropylmethoxy)-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (1.85 g, 0.004 mol) prepared in step 23-5 above (0.9 g, yield: 47.1%).

[0578] 1H-NMR (400 MHz, DMSO-d 6 ): 8.84-8.83 (m, 1H), 8.50-8.49 (m, 1H), 7.83-7.80 (m, 1H), 7.60-7.57 (m, 1H), 7.36 (s, 1H), 6.91-6.87 (m, 1H), 6.77-6.73 (m, 2H), 3.88-3.86 (d, 2H), 3.53 (s, 2H), 2.31 (s, 3H), 1.36-1.34 (m, 1H), 1.27-1.20 (m, 1H), 0.61-0.57 (m, 2H), 0.47-0.40 (m, 2H), 0.37-0.33 (m, 2H), 0.15-0.06 (m, 2H).

[0579] [M+H] + : 456.05

[0580]

[0581] Example 24: Preparation of 1-(4-cyclopropyl-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0582]

[0583]

[0584] Step 24-1: Preparation of methyl 4-cyclopropyl-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-1H-pyrrole-3-carboxylate

[0585] The title compound was prepared in the same manner as in step 1-4 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.012 mol) and 2-fluoro-4-(trifluoromethyl)phenyl)boronic acid (4.06 g, 0.018 mol) prepared in step 1-3 above (1.67 g, yield: 40.2%).

[0586] 1 H-NMR (400 MHz, DMSO-d 6): 11.55 (s, 1H), 7.59-7.55 (t, 1H), 7.49-7.46 (dd, 1H), 7.44-7.43 (d, 1H), 7.31-7.28 (m, 1H), 3.69 (s, 3H), 1.87-1.80 (m, 1H), 0.65-0.60 (m, 2H), 0.06-0.02 (m, 2H).

[0587]

[0588] Step 24-2: Preparation of methyl 4-cyclopropyl-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

[0589] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-1H-pyrrole-3-carboxylate (1.6 g, 0.005 mol) and pyridine-3-sulfonyl chloride (1.24 g, 0.007 mol) prepared in step 24-1 above (2.25 g, yield: 99.6%).

[0590] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.91-8.89 (dd, 1H), 8.57-8.56 (d, 1H), 8.15-8.12 (t, 1H), 7.98-7.95 (m, 1H), 7.62-7.59 (m, 1H), 7.40-7.39 (m, 1H), 7.30-7.24 (m, 2H), 3.78 (s, 3H), 1.76-1.69 (m, 1H), 0.53-0.47 (m, 2H), 0.10-0.06 (m, 2H).

[0591]

[0592] Step 24-3: Preparation of (4-cyclopropyl-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol

[0593] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (2.2 g, 0.005 mol) prepared in step 24-2 above (1.59 g, yield: 76.8%).

[0594] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.87-8.85 (dd, 1H), 8.53-8.52 (dd, 1H), 7.87-7.84 (m, 1H), 7.62-7.58 (m, 1H), 7.42-7.38 (m, 2H), 7.26-7.23 (m, 2H), 5.01-4.99 (t, 1H), 4.40-4.38 (d, 2H), 1.41-1.34 (m, 1H), 0.49-0.45 (m, 2H), 0.22-0.12 (m, 2H).

[0595]

[0596] Step 24-4: Preparation of 4-cyclopropyl-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0597] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol (1.5 g, 0.003 mol) prepared in step 24-3 above (1.07 g, yield: 71.8%).

[0598] 1 H-NMR (400 MHz, DMSO-d 6): 9.91 (s, 1H), 8.92-8.90 (dd, 1H), 8.59-8.58 (dd, 1H), 8.51 (s, 1H), 7.97-7.94 (m, 1H), 7.64-7.61 (qd, 1H), 7.42-7.39 (d, 1H), 7.31-7.25 (m, 2H), 1.68-1.61 (m, 1H), 0.58-0.53 (m, 2H), 0.30-0.26 (m, 2H).

[0599]

[0600] Step 24-5: Preparation of 1-(4-cyclopropyl-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0601] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (1.0 g, 0.002 mol) prepared in step 24-4 above (0.77 g, yield: 74.8%).

[0602] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.86-8.84 (m, 1H), 8.53-8.52 (d, 1H), 7.86-7.83 (m, 1H), 7.61-7.57 (m, 1H), 7.42-7.38 (m, 2H), 7.27-7.22 (m, 2H), 3.53 (s, 2H), 2.29 (s, 3H), 1.43-1.36 (m, 1H), 0.51-0.42 (m 2H), 0.14-0.03 (m, 2H).

[0603] [M+H] + : 469.99

[0604]

[0605] Example 25: Preparation of 1-(4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0606]

[0607]

[0608] Step 25-1: Preparation of methyl 4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrrole-3-carboxylate

[0609] The title compound was prepared in the same manner as in step 1-4 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.030 mol) and 2-fluoro-6-methoxyphenylboronic acid (6.16 g, 0.036 mol) prepared in step 1-3 above (2.6 g, yield: 29.8%).

[0610] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.22 (s, 1H), 7.41-7.37 (m, 1H), 7.35-7.34 (m, 1H), 6.92-6.90 (d, 1H), 6.87-6.82 (td, 1H), 3.73 (s, 3H), 1.84-1.78 (m, 1H), 0.50-0.45 (m, 2H), 0.11-0.07 (m, 2H).

[0611]

[0612] Step 25-2: Preparation of methyl 4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

[0613] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrrole-3-carboxylate (2.6 g, 0.009 mol) and pyridine-3-sulfonyl chloride (2.39 g, 0.014 mol) prepared in step 25-1 above (3.74 g, yield: 96.6%).

[0614] 1 H-NMR (400 MHz, DMSO-d 6): 8.89-8.88 (dd, 1H), 8.50-8.49 (d, 1H), 8.11 (s, 1H), 7.98-7.95 (m, 1H), 7.63-7.59 (qd, 1H), 7.54-7.48 (m, 1H), 6.82-6.78 (m, 2H), 3.78 (s, 3H), 3.42 (s, 3H), 1.81-1.74 (m, 1H), 0.47-0.44 (m, 2H), 0.14-0.10 (m, 2H).

[0615]

[0616] Step 25-3: Preparation of (4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol

[0617] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (3.74 g, 0.009 mol) prepared in step 25-2 above (1.16 g, yield: 33.1%).

[0618] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.84-8.83 (dd, 1H), 8.48-8.47 (d, 1H), 7.86-7.83 (m, 1H), 7.61-7.58 (qd, 1H), 7.49-7.43 (m, 1H), 7.38 (s, 1H), 6.82-6.76 (m, 2H), 4.98-4.95 (t, 1H), 4.40-4.38 (m, 2H), 3.40 (s, 3H), 1.34-1.30 (m, 1H), 0.12-0.39 (m, 2H), 0.20-0.17 (m, 2H).

[0619]

[0620] Step 25-4: Preparation of 4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0621] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol (1.16 g, 0.003 mol) prepared in step 25-3 above (0.24 g, yield: 20.9%).

[0622] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.89 (s, 1H), 8.91-8.89 (dd, 1H), 8.52-8.51 (d, 1H), 8.46 (s, 1H), 7.96-7.93 (m, 1H), 7.65-7.62 (m, 1H), 7.55-7.49 (m, 1H), 6.83-6.79 (m, 2H), 3.38 (s, 3H), 1.71-1.67 (m, 1H), 0.52-0.48 (m, 2H), 0.29-0.26 (m, 2H).

[0623]

[0624] Step 25-5: Preparation of 1-(4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0625] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.24 g, 0.0006 mol) prepared in step 25-4 above (20 mg, yield: 8.0%).

[0626] 1 H-NMR (400 MHz, DMSO-d 6): 8.85-8.84 (dd, 1H), 8.49-8.48 (m, 1H), 7.85-7.82 (m, 1H), 7.62-7.59 (m, 1H), 7.48-7.44 (m, 2H), 6.83-6.77 (m, 2H), 3.65 (s, 2H), 3.42 (s, 3H), 2.41 (s, 3H), 1.37-1.32 (m, 1H), 0.44-0.39 (m, 2H), 0.13-0.12(m, 2H).

[0627] [M+H] + : 416.33

[0628]

[0629] Example 26: Preparation of 1-(4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0630]

[0631]

[0632] Step 26-1: Preparation of methyl 4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carboxylate

[0633] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1H-pyrrole-3-carboxylate (1.5 g, 0.005 mol) and 3-fluorophenylsulfonyl chloride (1.51 g, 0.008 mol) prepared in step 25-1 above (1.33 g, yield: 57.6%).

[0634] 1 H-NMR (400 MHz, DMSO-d 6): 8.09 (s, 1H), 7.64-7.58 (m, 2H), 7.54-7.48 (m, 1H), 7.36-7.32 (m, 2H), 6.83-6.77 (m, 2H), 3.77 (s, 3H), 3.43 (s, 3H), 1.80-1.73 (m, 1H), 0.47-0.44 (m, 2H), 0.15-0.11 (m, 2H).

[0635]

[0636] Step 26-2: Preparation of (4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)methanol

[0637] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carboxylate (1.33 g, 0.003 mol) prepared in step 26-1 above (1.16 g, yield: 93.5%).

[0638] 1 H-NMR (400 MHz, DMSO-d 6 ): 7.64-7.57 (m, 2H), 7.48-7.42 (m, 1H), 7.35-7.30 (m, 2H), 7.17-7.14 (m, 1H), 6.84-6.76 (m, 2H), 4.97-4.94 (t, 1H), 4.39-4.38 (d, 2H), 3.48 (s, 3H), 1.34-1.14 (m, 1H), 0.42-0.38 (m, 2H), 0.20-0.17 (m, 2H).

[0639]

[0640] Step 26-3: Preparation of 4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde

[0641] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)methanol (1.16 g, 0.003 mol) prepared in step 26-2 above. (1.11 g, yield: 96.5%)

[0642] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.88 (s, 1H), 8.43 (s, 1H), 7.68-7.61 (m, 2H), 7.54-7.48 (m, 1H), 7.37-7.33 (m, 1H), 7.28-7.26 (m, 1H), 6.84-6.78 (m, 2H), 3.43 (s, 3H), 1.72-1.65 (m, 1H), 0.54-0.45 (m, 2H), 0.34-0.26 (m, 2H).

[0643]

[0644] Step 26-4: Preparation of 1-(4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0645] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde (1.11 g, 0.003 mol) prepared in step 26-3 above (0.57 g, yield: 45.6%).

[0646] 1 H-NMR (400 MHz, DMSO-d 6): 7.63-7.54 (m, 2H), 7.48-7.42 (m, 1H), 7.38 (s, 1H), 7.32-7.29 (m, 1H), 7.16-7.13 (m, 1H), 6.83-6.75 (m, 2H), 3.58 (s, 2H), 3.47 (s, 3H), 2.36 (s, 3H), 1.37-1.30 (m, 1H), 0.45-0.36 (m, 2H), 0.14-0.09 (m, 2H).

[0647] [M+H] + : 433.03

[0648]

[0649] Example 27: Preparation of 1-(4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0650]

[0651]

[0652] Step 27-1: Preparation of methyl 4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-1H-pyrrole-3-carboxylate

[0653] The title compound was prepared in the same manner as in step 1-4 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.021 mol) and 2-fluoro-4-methoxybenzeneboronic acid (5.44 g, 0.032 mol) prepared in step 1-3 above (3.71 g, yield: 60.6%).

[0654] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.37 (s, 1H), 7.35-7.30 (m, 2H), 6.91-6.81 (m, 2H), 3.79 (s, 3H), 3.68 (s, 3H), 1.85-1.81 (m, 1H), 0.51-0.56 (m, 2H), 0.09-0.05 (m, 2H).

[0655]

[0656] Step 27-2: Preparation of methyl 4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

[0657] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-1H-pyrrole-3-carboxylate (3.0 g, 0.010 mol) and pyridine-3-sulfonyl chloride (2.76 g, 0.016 mol) prepared in step 27-1 above (4.44 g, yield: 99.6%).

[0658] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.89-8.87 (dd, 1H), 8.54-8.53 (d, 1H), 8.08 (s, 1H), 7.94-7.90 (m, 1H), 7.62-7.58 (qd, 1H), 6.95-6.90 (t, 1H), 6.78-6.75 (m, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 1.79-1.72 (m, 1H), 0.53-0.44 (m, 2H), 0.15-0.07 (m, 2H).

[0659]

[0660] Step 27-3: Preparation of (4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol

[0661] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (4.44 g, 0.010 mol) prepared in step 27-2 above (2.22 g, yield: 54.0%).

[0662] 1 H-NMR (400 MHz, DMSO-d 6): 8.85-8.83 (dd, 1H), 8.50-8.49 (d, 1H), 7.83-7.80 (m, 1H), 7.61-7.57 (m, 1H), 7.36 (s, 1H), 6.94-6.90 (t, 1H), 6.80-6.75 (m, 2H), 4.99-4.96 (t, 1H), 4.39-4.38 (d, 2H), 3.80 (s, 3H), 1.39-1.32 (m, 1H), 0.47-0.42 (m, 2H), 0.20-0.16 (m, 2H).

[0663]

[0664] Step 27-4: Preparation of 4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0665] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol (2.2 g, 0.005 mol) prepared in step 27-3 above (1.36 g, yield: 62.1%).

[0666] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.77 (s, 1H), 8.91-8.88 (m, 2H), 8.44-8.42 (m, 1H), 7.78-7.67 (m, 2H), 7.10 (s, 1H), 6.85-6.80 (m, 2H), 3.92 (s, 3H), 2.28-2.19 (m, 1H), 1.32-1.28 (m, 2H), 1.01-0.97 (m, 2H).

[0667]

[0668] Step 27-5: Preparation of 1-(4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0669] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.7 g, 0.002 mol) prepared in step 27-4 above (0.69 g, yield: 94.5%).

[0670] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.84-8.82 (m, 1H), 8.49-8.48 (m, 1H), 7.82-7.79 (m, 1H), 7.60-7.56 (m, 1H), 7.36 (s, 1H), 6.93-6.89 (m, 1H), 6.80-6.74 (m, 2H), 3.81 (s, 3H), 3.53 (s, 2H), 2.30 (s, 3H), 1.41-1.34 (m, 1H), 0.47-0.42 (m, 2H), 0.12-0.08 (m, 2H).

[0671] [M+H] + : 415.98

[0672]

[0673] Example 28: Preparation of 1-(4-cyclopropyl-5-(2,4-difluorophenyl)1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0674]

[0675]

[0676] Step 28-1: Preparation of methyl 4-cyclopropyl-5-(2,4-difluorophenyl)-1H-pyrrole-3-carboxylate

[0677] The title compound was prepared in the same manner as in step 22-2 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.066 mol) and 2,4-difluorophenylboronic acid (12.48 g, 0.079 mol) prepared in step 1-3 above (8.7 g, yield: 45.4%).

[0678] 1H-NMR (400 MHz, DMSO-d 6 ): 11.51 (s, 1H), 7.50-7.44 (m, 1H), 7.41 (s, 1H), 7.36-7.30 (td, 1H), 7.17-7.12 (td, 1H), 3.69 (s, 3H), 1.84-1.80 (m, 1H), 0.63-0.58 (m, 2H), 0.06-0.02 (m, 2H).

[0679]

[0680] Step 28-2: Preparation of (4-cyclopropyl-5-(2,4-difluorophenyl)-1H-pyrrol-3-yl)methanol

[0681] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2,4-difluorophenyl)-1H-pyrrole-3-carboxylate (8.7 g, 0.030 mol) prepared in step 28-1 above (7.0 g, yield: 94.1%).

[0682] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.95 (s, 1H), 7.75-7.72 (m, 1H), 7.09-7.06 (m, 1H), 6.89-6.86 (m, 1H), 6.42 (s, 1H), 5.12 (t, 1H), 4.57 (d, 2H), 2.27-2.22 (m, 1H), 1.12-1.08 (m, 2H), 0.93-0.89 (m, 2H).

[0683]

[0684] Step 28-3: Preparation of 4-cyclopropyl-5-(2,4-difluorophenyl)-1H-pyrrole-3-carbaldehyde

[0685] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(2,4-difluorophenyl)-1H-pyrrol-3-yl)methanol (7.0 g, 0.028 mol) prepared in step 28-2 above (3.33 g, yield: 47.9%).

[0686] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.78 (s, 1H), 9.80 (s, 1H), 7.60 (s, 1H), 7.55-7.48 (m, 1H), 7.39-7.33 (td, 1H), 7.20-7.15 (td, 1H), 1.84-1.77 (m, 1H), 0.68-0.63 (m, 2H), 0.28-0.24 (m, 2H).

[0687]

[0688] Step 28-4: Preparation of 4-cyclopropyl-5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0689] The title compound was prepared in the same manner as in step 1-5 using 4-cyclopropyl-5-(2,4-difluorophenyl)-1H-pyrrole-3-carbaldehyde (0.6 g, 0.004 mol) and pyridine-3-sulfonyl chloride (1.07 g, 0.006 mol) prepared in step 28-3 above (0.9 g, yield: 95.7%).

[0690] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.91 (s, 1H), 8.92-8.90 (dd, 1H), 8.60-8.59 (d, 1H), 8.46 (s, 1H), 7.97-7.94 (m, 1H), 7.66-7.62 (m, 1H), 7.29-7.23 (m, 1H), 7.18-7.09 (m, 2H), 1.67-1.63 (m, 1H), 0.57-0.52 (m, 2H), 0.29-0.25 (m, 2H).

[0691]

[0692] Step 28-5: Preparation of 1-(4-cyclopropyl-5-(2,4-difluorophenyl)1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0693] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.87 g, 0.002 mol) prepared in step 28-4 above (0.29 g, yield: 49.0%).

[0694] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.86-8.85 (dd, 1H), 8.54-8.53 (m, 1H), 7.86-7.83 (m, 1H), 7.62-7.58 (m, 1H), 7.50 (s, 1H), 7.28-7.23 (m, 1H), 7.12-7.09 (m, 2H), 3.65 (s, 2H), 3.37 (s, 3H), 1.44-1.40 (m, 1H), 0.49-0.46 (m, 2H), 0.10-0.06 (m, 2H).

[0695] [M+H] + : 403.99

[0696]

[0697] Example 29: Preparation of 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0698]

[0699]

[0700] Step 29-1: Preparation of methyl 4-cyclopropyl-5-(2,4-difluorophenyl)-1H-pyrrole-3-carboxylate

[0701] The title compound was prepared in the same manner as in step 1-4 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.091 mol) and 2,4-difluorophenylboronic acid (18.62 g, 0.118 mol) prepared in step 1-3 above (7.18 g, yield: 30.6%).

[0702] 1H-NMR (400 MHz, DMSO-d 6 ): 11.50 (s, 1H), 7.49-7.46 (m, 1H), 7.41 (s, 1H), 7.34-7.32 (td, 1H), 7.15-7.14 (td, 1H), 3.88 (s, 3H), 1.85-1.81 (m, 1H), 0.63-0.60 (m, 2H), 0.06-0.04 (m, 2H).

[0703]

[0704] Step 29-2: Preparation of methyl 4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carboxylate

[0705] The title compound was prepared in the same manner as in step 6-2 using methyl 4-cyclopropyl-5-(2,4-difluorophenyl)-1H-pyrrole-3-carboxylate (7.0 g, 0.027 mol) and 6-methoxypyridine-3-sulfonyl chloride (7.29 g, 0.035 mol) prepared in step 29-1 above (11.76 g, yield: 97.2%).

[0706] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.17-8.16 (d, 1H), 8.08-8.06 (d, 1H), 7.82-7.79 (dd, 1H), 7.30-7.10 (m, 3H), 6.98-6.95 (d, 1H), 3.93 (s, 3H), 3.78 (s, 3H), 1.76-7.72 (m, 1H), 0.52-1.49 (m, 2H), 0.13-0.08 (m, 2H).

[0707]

[0708] Step 29-3: Preparation of (4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methanol

[0709] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carboxylate (11.0 g, 0.025 mol) prepared in step 29-2 above (5.3 g, yield: 51.4%).

[0710] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.15-8.14 (d, 1H), 7.70-7.67 (dd, 1H), 7.36 (s, 1H), 7.29-7.23 (td, 1H), 7.16-7.09 (m, 2H), 6.97-6.95 (d, 1H), 4.98-4.96 (t, 1H), 4.40-4.39 (d, 2H), 3.92 (s, 3H), 1.40-1.35 (m, 1H), 0.49-0.44 (m, 2H), 0.19-0.16 (m, 2H).

[0711]

[0712] Step 29-4: Preparation of 4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carbaldehyde

[0713] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methanol (3.0 g, 0.007 mol) prepared in step 29-3 above (3.5 g, yield: 66.4%).

[0714] 1 H-NMR (400 MHz, DMSO-d 6): 9.90 (s, 1H), 8.43 (s, 1H), 8.18-8.17 (d, 1H), 7.80-7.78 (dd, 1H), 7.32-7.26 (td, 1H), 7.21-7.13 (m, 2H), 7.00-6.98 (d, 1H), 3.94 (s, 3H), 1.68-1.63 (m, 1H), 0.57-0.53 (m, 2H), 0.30-0.28 (m, 2H).

[0715]

[0716] Step 29-5: Preparation of 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0717] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carbaldehyde (2.0 g, 0.005 mol) prepared in step 29-4 above (1.83 g, yield: 88.4%).

[0718] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.14-8.13 (d, 1H), 7.69-7.67 (dd, 1H), 7.36 (s, 1H), 7.28-7.25 (td, 1H), 7.15-7.10 (m, 2H), 6.96-6.94 (d, 1H), 3.52 (s, 2H), 2.31 (s, 3H), 1.42-1.37 (m, 1H), 0.48-0.45 (m, 2H), 0.12-0.09 (m, 2H).

[0719] [M+H] + : 434.01

[0720]

[0721] Example 30: Preparation of 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methylpyridin-3-yl)-sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0722]

[0723]

[0724] Step 30-1: Preparation of 4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methylpyridin-3-yl)-sulfonyl)-1H-pyrrole-3-carbaldehyde

[0725] The title compound was prepared in the same manner as in step 1-5 using 4-cyclopropyl-5-(2,4-difluorophenyl)-1H-pyrrole-3-carbaldehyde (0.3 g, 0.001 mol) and 6-methylpyridine-3-sulfonyl chloride (0.35 g, 0.002 mol) prepared in step 28-3 above (0.45 g, yield: 88.0%).

[0726] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.89 (s, 1H), 8.46 (s, 1H), 8.18-8.17 (d, 1H), 7.84-7.81 (dd, 1H), 7.50-7.47 (d, 1H), 7.30-7.10 (m, 3H), 2.56 (s, 3H), 1.67-1.62 (m, 1H), 0.55-0.53 (m, 2H), 0.29-0.26 (m, 2H).

[0727]

[0728] Step 30-2: Preparation of 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methylpyridin-3-yl)-sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0729] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methylpyridin-3-yl)-sulfonyl)-1H-pyrrole-3-carbaldehyde (0.45 g, 0.001 mol) prepared in step 30-1 above (0.38 g, yield: 80.4%).

[0730] 1 H-NMR (400 MHz, DMSO-d 6): 8.46-8.45 (d, 1H), 7.66-7.63 (dd, 1H), 7.48 (s, 1H), 7.26 (s, 1H), 7.19-7.10 (m, 1H), 6.93-6.89 (td, 1H), 6.82-6.77 (td, 1H), 3.79 (s, 2H), 2.56 (s, 3H), 1.42-1.38 (m, 1H), 0.55-0.47 (m, 2H), 0.15-0.11 (m, 2H).

[0731] [M+H] + : 418.00

[0732]

[0733] Example 31: Preparation of 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl-1H-pyrrol-3-yl)-N-methylmethanamine

[0734]

[0735]

[0736] Step 31-1: Preparation of 4-cyclopropyl-5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde

[0737] The title compound was prepared in the same manner as in step 1-5 using 4-cyclopropyl-5-(2,4-difluorophenyl)-1H-pyrrole-3-carbaldehyde (0.3 g, 0.001 mol) and 3-fluorophenylsulfonyl chloride (0.35 g, 0.002 mol) prepared in step 28-3 above (0.47 g, yield: 96.0%).

[0738] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.90 (s, 1H), 8.46 (s, 1H), 7.67-7.63 (m, 2H), 7.33-7.29 (m, 2H), 7.27-7.24 (td, 1H), 7.15-7.09 (m, 2H), 1.67-1.63 (m, 1H), 0.56-0.52 (m, 2H), 0.29-0.25 (m, 2H).

[0739]

[0740] Step 31-2: Preparation of 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl-1H-pyrrol-3-yl)-N-methylmethanamine

[0741] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde (0.46 g, 0.001 mol) prepared in step 31-1 above (0.23 g, yield: 48.6%).

[0742] 1 H-NMR (400 MHz, DMSO-d 6 ): 7.64-7.57 (m, 2H), 7.45 (s, 1H), 7.28-7.19 (m, 3H), 7.12-7.06 (m, 2H), 3.64 (s, 2H), 2.37 (s, 3H), 1.43-1.38 (m, 1H), 0.48-0.46 (m, 2H), 0.10-0.05 (m, 2H).

[0743] [M+H] + : 421.03

[0744]

[0745] Example 32: Preparation of 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride

[0746]

[0747]

[0748] The title compound was prepared in the same manner as in Example 7 using 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl-1H-pyrrol-3-yl)-N-methylmethanamine (0.5 g, 0.001 mol) prepared in step 31-2 above (0.29 g, yield: 51.8%).

[0749] 1 H-NMR (400 MHz, CD3OD): 7.73 (s, 1H), 7.56-7.51 (m, 1H), 7.47-7.43 (m, 1H), 7.30-7.28 (m, 1H), 7.18-7.07 (m, 2H), 7.03-6.92 (m, 2H), 4.20 (s, 2H), 2.79 (s, 3H), 1.52-1.45 (m, 1H), 0.63-0.58 (m, 2H), 0.18-0.13 (m, 2H).

[0750] [M+H] + : 420.97

[0751]

[0752] Example 33: Preparation of 1-(4-cyclopropyl-5-(2-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0753]

[0754]

[0755] Step 33-1: Preparation of methyl 4-cyclopropyl-5-(2-methoxyphenyl)-1H-pyrrole-3-carboxylate

[0756] The title compound was prepared in the same manner as in step 1-4 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.018 mol) and 2-methoxyphenylboronic acid (3.30 g, 0.022 mol) prepared in step 1-3 above (3.36 g, yield: 68.4%).

[0757] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.14 (s, 1H), 7.33 (m, 2H), 7.05-7.03 (d, 1H), 6.98-6.94 (td, 1H), 6.41-6.40 (t, 1H), 3.73 (s, 3H), 3.67 (s, 3H), 0.57-0.51 (m, 2H), 0.08-0.04 (m, 2H).

[0758]

[0759] Step 33-2: Preparation of methyl 4-cyclopropyl-5-(2-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

[0760] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(2-methoxyphenyl)-1H-pyrrole-3-carboxylate (3.36 g, 0.012 mol) and pyridine-3-sulfonyl chloride (3.30 g, 0.019 mol) prepared in step 33-1 above (2.0 g, yield: 39.2%).

[0761] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.86-8.85 (dd, 1H), 8.42-8.41 (d, 1H), 8.03 (s, 1H), 7.88-7.85 (m, 1H), 7.59-7.55 (m, 1H), 7.45-7.41 (m, 1H), 6.92-6.91 (d, 2H), 6.88-6.86 (d, 1H), 3.77 (s, 3H), 3.33 (s, 3H), 1.79-1.73 (m, 1H), 0.43-0.37 (m, 2H), 0.12-0.08 (m, 2H).

[0762]

[0763] Step 33-3: Preparation of (4-cyclopropyl-5-(2-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol

[0764] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (2.0 g, 0.005 mol) prepared in step 33-2 above (1.84 g, yield: 98.9%).

[0765] 1 H-NMR (400 MHz, DMSO-d 6): 8.82-8.81 (dd, 1H), 8.42-8.41 (d, 1H), 7.78-7.75 (m, 1H), 7.58-7.55 (m, 1H), 7.41-7.37 (td, 1H), 7.31 (s, 1H), 6.92-6.87 (m, 3H), 4.96-4.93 (t, 1H), 4.39-4.38 (d, 2H), 1.34-1.30 (m, 1H), 0.39-0.34 (m, 2H), 0.17-0.16 (m, 2H).

[0766]

[0767] Step 33-4: Preparation of 4-cyclopropyl-5-(2-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0768] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(2-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol (1.84 g, 0.005 mol) prepared in step 33-3 above (0.2 g, yield: 10.9%).

[0769] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.88 (s, 1H), 8.88-8.86 (dd, 1H), 8.44-8.43 (d, 1H), 8.39 (s, 1H), 7.87-7.84 (m, 1H), 7.61-7.58 (qd, 1H), 7.46-7.42 (m, 1H), 6.94-6.88 (m, 3H), 3.34 (s, 3H), 1.71-1.64 (m, 1H), 0.49-0.42 (m, 2H), 0.28-0.26 (m, 2H).

[0770]

[0771] Step 33-5: Preparation of 1-(4-cyclopropyl-5-(2-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0772] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (80 mg, 0.2 mmol) prepared in step 33-4 (0.53 g, yield: 63.9%).

[0773] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.83-8.81 (dd, 1H), 8.43-8.42 (m, 1H), 7.78-7.75 (m, 1H), 7.58-7.55 (m, 1H), 7.42-7.37 (m, 2H), 6.92-6.84 (m, 3H), 3.67 (s, 2H), 3.40 (s, 3H), 2.41 (s, 3H), 1.39-1.31 (m, 1H), 0.45-0.31 (m, 2H), 0.13-0.04 (m, 2H).

[0774] [M+H] + : 398.02

[0775]

[0776] Example 34: Preparation of 1-(4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-methoxyphenyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0777]

[0778]

[0779] Step 34-1: Preparation of methyl 4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-methoxyphenyl)-1H-pyrrole-3-carboxylate

[0780] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(2-methoxyphenyl)-1H-pyrrole-3-carboxylate (3.36 g, 0.012 mol) and 3-fluorophenylsulfonyl chloride (0.35 g, 0.002 mol) prepared in step 33-1 above (1.65 g, yield: 24.0%).

[0781] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.01 (s, 1H), 7.63-7.55 (m, 2H), 7.45-7.41 (m, 1H), 7.30-7.27 (m, 1H), 7.18-7.15 (m, 1H), 6.92-6.86 (m, 3H), 3.77 (s, 3H), 3.40 (s, 3H), 1.80-1.73 (m, 1H), 0.45-0.36 (m, 2H), 0.14-0.08 (m, 2H).

[0782]

[0783] Step 34-2: Preparation of (4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-methoxyphenyl)-1H-pyrrol-3-yl)methanol

[0784] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-methoxyphenyl)-1H-pyrrole-3-carboxylate (0.65 g, 0.004 mol) prepared in step 34-1 above (1.53 g, yield: 100.0%).

[0785] 1 H-NMR (400 MHz, DMSO-d 6 ): 7.60-7.55 (m, 2H), 7.41-7.37 (m, 1H), 7.28-7.24 (m, 2H), 7.08-7.05 (m, 1H), 6.94-6.85 (m, 3H), 4.95-4.92 (t, 1H), 4.39-4.37 (dd, 2H), 0.34-0.30 (m, 1H), 0.40-0.32 (m, 2H), 0.18-0.16 (m, 2H).

[0786]

[0787] Step 34-3: Preparation of 4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-methoxyphenyl)-1H-pyrrole-3-carbaldehyde

[0788] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-methoxyphenyl)-1H-pyrrol-3-yl)methanol (1.53 g, 0.004 mol) prepared in step 34-2 above (1.0 g, yield: 61.0%).

[0789] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.87 (s, 1H), 8.36 (s, 1H), 7.65-7.57 (m, 2H), 7.46-7.41 (m, 1H), 7.31-7.28 (m, 1H), 7.17-7.14 (m, 1H), 6.93-6.87 (m, 3H), 3.41 (s, 3H), 1.71-1.63 (m, 1H), 0.49-0.41 (m, 2H), 0.31-0.26 (m, 2H).

[0790]

[0791] Step 34-4: Preparation of 1-(4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-methoxyphenyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0792] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-methoxyphenyl)-1H-pyrrole-3-carbaldehyde (1.0 g, 0.003 mol) prepared in step 34-3 above (0.19 g, yield: 18.4%).

[0793] 1 H-NMR (400 MHz, DMSO-d 6): 7.60-7.52 (m, 2H), 7.41-7.36 (m, 1H), 7.31 (s, 1H), 7.25-7.23 (dt, 1H), 7.07-7.04 (m, 1H), 6.93-6.87 (m, 2H), 6.84-6.82 (m, 1H), 3.57 (s, 2H), 3.46 (s, 3H), 2.35 (s, 3H), 1.38-1.31 (m, 1H), 0.43-0.30 (m, 2H), 0.14-0.06 (m, 2H).

[0794] [M+H] + : 414.98

[0795]

[0796] Example 35: Preparation of 1-(4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0797]

[0798]

[0799] Step 35-1: Preparation of methyl 4-cyclopropyl-5-(pyridin-4-yl)-1H-pyrrole-3-carboxylate

[0800] The title compound was prepared in the same manner as in step 1-4 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.021 mol) and 4-pyridinylboronic acid (3.06 g, 0.025 mol) prepared in step 1-3 above. (4.82 g, yield: 96.0%)

[0801] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.83 (s, 1H), 8.56-8.54 (m, 2H), 7.58-7.56 (dd, 2H), 7.49 (s, 1H), 3.71 (s, 3H), 1.97-1.85 (m, 1H), 0.89-0.83 (m, 2H), 0.15-0.09 (m, 2H).

[0802]

[0803] Step 35-2: Preparation of methyl 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrole-3-carboxylate

[0804] The title compound was prepared in the same manner as in Step 1-5 using methyl 4-cyclopropyl-5-(pyridin-4-yl l)-1H-pyrrole-3-carboxylate (8.82 g, 0.036 mol) and pyridine-3-sulfonyl chloride (9.70 g, 0.055 mol) prepared in Step 35-1 above. (13.0 g, yield: 93.2%)

[0805] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.91-8.90 (m, 1H), 8.82-8.78 (m, 2H), 8.55-8.52 (m, 1H), 8.20 (s, 1H), 8.05-8.02 (m, 1H), 7.93-7.89 (m, 1H), 7.63-7.60 (m, 2H), 3.78 (s, 3H), 1.76-1.71 (m, 1H), 0.56-0.51 (m, 2H), 0.01-0.00 (m, 2H).

[0806]

[0807] Step 35-3: Preparation of (4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrol-3-yl)methanol

[0808] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrole-3-carboxylate (15.0 g, 0.039 mol) prepared in step 35-2 above (1.3 g, yield: 9.4%).

[0809] 1 H-NMR (400 MHz, DMSO-d 6): 8.86-8.85 (dd, 1H), 8.59-8.53 (m, 2H), 7.84-7.81 (m, 1H), 7.61-7.60 (m, 2H), 7.40 (s, 1H), 7.16-7.11 (m, 2H), 5.51-5.03 (t, 1H), 4.39-4.37 (d, 2H), 1.49-1.44 (m, 1H), 0.51-0.47 (m, 2H), 0.16-0.08 (m, 2H).

[0810]

[0811] Step 35-4: Preparation of 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrole-3-carbaldehyde

[0812] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrol-3-yl)methanol (1.30 g, 0.004 mol) prepared in step 35-3 above (0.27 g, yield: 20.9%).

[0813] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.92 (s, 1H), 8.91-8.90 (dd, 1H), 8.61-8.58 (m, 3H), 8.49 (s, 1H), 7.93-7.92 (m, 1H), 7.64-7.61 (m, 1H), 7.13-7.12 (m, 2H), 1.67-1.63 (m, 1H), 0.56-0.52 (m, 2H), 0.25-0.21 (m, 2H).

[0814]

[0815] Step 35-5: Preparation of 1-(4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0816] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrole-3-carbaldehyde (0.27 g, 0.001 mol) prepared in step 35-4 above (0.08 g, yield: 28.6%).

[0817] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.87-8.84 (m, 1H), 8.60-8.53 (m, 3H), 7.83-7.80 (m, 1H), 7.60-7.57 (m, 1H), 7.42 (s, 1H), 7.19-7.15 (m, 2H), 3.53 (s, 2H), 2.27 (s, 3H), 1.51-1.46 (m, 1H), 0.51-0.48 (m, 2H), 0.08-0.00 (m, 2H).

[0818] [M+H] + : 368.97

[0819]

[0820] Example 36: Preparation of 1-(4-cyclopropyl-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0821]

[0822]

[0823] Step 36-1: Preparation of methyl 4-cyclopropyl-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carboxylate

[0824] The title compound was prepared in the same manner as in step 1-4 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.024 mol) and 2-fluoropyridine-3-boronic acid (4.09 g, 0.029 mol) prepared in step 1-3 above (1.60 g, yield: 25.4%).

[0825] 1 H-NMR (400 MHz, DMSO-d 6): 11.62 (s, 1H), 8.21-8.19 (m, 1H), 8.03-7.98 (m, 1H), 7.45 (s, 1H), 7.43-7.40 (m, 1H), 3.70 (s, 3H), 1.88-1.81 (m, 1H), 0.67-0.63 (m, 2H), 0.04-0.00 (m, 2H).

[0826]

[0827] Step 36-2: Preparation of methyl 4-cyclopropyl-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

[0828] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carboxylate (1.60 g, 0.006 mol) and pyridine-3-sulfonyl chloride (1.64 g, 0.009 mol) prepared in step 36-1 above (1.68 g, yield: 68.0%).

[0829] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.92-8.90 (dd, 1H), 8.61-8.60 (d, 1H), 8.37-8.36 (dt, 1H), 8.17 (s, 1H), 8.00-7.97 (m, 1H), 7.80-7.75 (m, 1H), 7.65-7.61 (m, 1H), 7.44-7.41 (m, 1H), 3.78 (s, 3H), 1.75-1.68 (m, 1H), 0.53-0.47 (m, 2H), 0.11-0.00 (m, 2H).

[0830]

[0831] Step 36-3: Preparation of (4-cyclopropyl-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol

[0832] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (1.68 g, 0.004 mol) prepared in step 36-2 above (1.49 g, yield: 95.5%).

[0833] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.88-8.86 (dd, 1H), 8.55-8.54 (d, 1H), 8.26-8.25 (m, 1H), 7.87-7.79 (m, 1H), 7.63-7.60 (m, 1H), 7.43-7.33 (m, 2H), 7.13 (s, 1H), 6.42-6.40 (dd, 1H), 4.42-4.38 (s, 2H), 1.48-1.38 (m, 1H), 0.61-0.43 (m, 2H), 0.23-0.17 (m, 2H).

[0834]

[0835] Step 36-4: Preparation of 4-cyclopropyl-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0836] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol (2.09 g, 0.006 mol) prepared in step 36-3 above (0.36 g, yield: 17.3%).

[0837] 1 H-NMR (400 MHz, DMSO-d 6): 9.91 (s, 1H), 8.93-8.92 (dd, 1H), 8.62-8.61 (m, 1H), 8.52 (s, 1H), 8.38-8.36 (m, 1H), 7.98-7.94 (m, 1H), 7.81-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.48-7.41 (m, 1H), 1.66-1.64 (m, 1H), 0.57-0.55 (m, 2H), 0.28-0.22 (m, 2H).

[0838]

[0839] Step 36-5: Preparation of 1-(4-cyclopropyl-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0840] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.36 g, 0.001 mol) prepared in step 36-4 above (0.05 g, yield: 13.5%).

[0841] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.87-8.86 (dd, 1H), 8.55-8.54 (d, 1H), 8.32-8.31 (m, 1H), 7.86-7.83 (m, 1H), 7.34-7.69 (m, 1H), 7.63-7.59 (m, 1H), 7.47 (s, 1H), 7.43-7.39 (m, 1H), 3.58 (s, 2H), 2.32 (s, 3H), 1.46-1.39 (m, 1H), 0.51-0.43 (m, 2H), 0.15-0.00 (m, 2H).

[0842] [M+H] + : 386.91

[0843]

[0844] Example 37: Preparation of 1-(4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0845]

[0846]

[0847] Step 37-1: Preparation of methyl 4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carboxylate

[0848] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carboxylate (1.87 g, 0.007 mol) and 3-fluorophenylsulfonyl chloride (2.10 g, 0.011 mol) prepared in step 36-1 above (2.73 g, yield: 90.7%).

[0849] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.38-8.34 (dd, 1H), 8.16-8.15 (d, 1H), 7.77-7.75 (m, 1H), 7.68-7.63 (m, 2H), 7.44-7.42 (m, 2H), 7.34-7.31 (m, 1H), 3.79 (s, 3H), 1.74-1.70 (m, 1H), 0.53-0.48 (m, 2H), 0.09-0.04 (m, 2H).

[0850]

[0851] Step 37-2: Preparation of (4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl)methanol

[0852] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carboxylate (2.73 g, 0.007 mol) prepared in step 37-1 above (2.26 g, yield: 89.0%).

[0853] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.33-8.31 (dd, 1H), 7.73-7.72 (m, 1H), 7.65-7.61 (m, 2H), 7.43-7.41 (m, 2H), 7.29-7.24 (m, 2H), 5.04-5.01 (t, 1H), 4.40-4.39 (d, 2H), 1.42-1.38 (m, 1H), 0.50-0.46 (m, 2H), 0.19-0.11 (m, 2H).

[0854]

[0855] Step 37-3: Preparation of 4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde

[0856] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl)methanol (2.26 g, 0.006 mol) prepared in step 37-2 above (0.9 g, yield: 40.0%).

[0857] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.91 (s, 1H), 8.51 (s, 1H), 8.39-8.37 (m, 1H), 7.78-7.65 (m, 3H), 7.44-7.32 (m, 3H), 1.67-1.61 (m, 1H), 0.58-0.55 (m, 2H), 0.28-0.24 (m, 2H).

[0858]

[0859] Step 37-4: Preparation of 1-(4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0860] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (0.9 g, 0.002 mol) prepared in step 37-3 above (0.32 g, yield: 34.4%).

[0861] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.33-8.31 (dd, 1H), 7.72-7.61 (m, 3H), 7.46 (s, 1H), 7.41-7.39 (m, 1H), 7.27-7.23 (m, 2H), 3.60 (s, 2H), 2.33 (s, 3H), 1.46-1.41 (m, 1H), 0.51-0.46 (m, 2H), 0.12-0.03 (m, 2H).

[0862] [M+H] + : 403.98

[0863]

[0864] Example 38: Preparation of 1-(4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyrimidin-5-yl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0865]

[0866]

[0867] Step 38-1: Preparation of methyl 4-cyclopropyl-5-(pyrimidin-5-yl)-1H-pyrrole-3-carboxylate

[0868] The title compound was prepared in the same manner as in step 1-4 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.030 mol) and 5-pyrimidinylboronic acid (4.50 g, 0.036 mol) prepared in step 1-3 above (2.80 g, yield: 38.0%).

[0869] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.91 (s, 1H), 9.10 (s, 1H), 9.08-8.56 (m, 2H), 7.56 (s, 1H), 3.72 (s, 3H), 1.99-1.92 (m, 1H), 0.86-0.80 (m, 2H), 0.09-0.05 (m, 2H).

[0870]

[0871] Step 38-2: Preparation of methyl 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyrimidin-5-yl)-1H-pyrrole-3-carboxylate

[0872] The title compound was prepared in the same manner as in step 1-5 using methyl 4-cyclopropyl-5-(pyrimidin-5-yl)-1H-pyrrole-3-carboxylate (2.80 g, 0.012 mol) and pyridine-3-sulfonyl chloride (3.07 g, 0.017 mol) prepared in step 38-1 above (2.64 g, yield: 59.7%).

[0873] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.26 (s, 1H), 8.92-8.90 (dd, 1H), 8.62-8.60 (m, 3H), 8.19 (s, 1H), 7.96-7.93 (m, 1H), 7.65-7.61 (m, 1H), 3.79 (s, 3H), 1.77-1.72 (m, 2H), 0.56-0.51 (m, 2H), 0.03-0.00 (m, 2H).

[0874]

[0875] Step 38-3: Preparation of (4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyrimidin-5-yl)-1H-pyrrol-3-yl)methanol

[0876] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyrimidin-5-yl)-1H-pyrrole-3-carboxylate (2.64 g, 0.007 mol) prepared in step 38-2 above (2.33 g, yield: 95.1%).

[0877] 1 H-NMR (400 MHz, DMSO-d 6 ): 10.21 (s, 1H), 8.88-8.87 (m, 1H), 8.11-8.08 (m, 1H), 7.65-7.63 (m, 1H), 7.19-7.07 (m, 2H), 5.69 (s, 1H), 4.96-4.91 (m, 1H), 4.33-4.28 (m, 2H), 3.89 (s, 1H), 1.45-1.41 (m, 1H), 0.66-0.65 (m, 2H), 0.48-0.47 (m, 2H).

[0878]

[0879] Step 38-4: Preparation of 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyrimidin-5-yl)-1H-pyrrole-3-carbaldehyde

[0880] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyrimidin-5-yl)-1H-pyrrol-3-yl)methanol (2.33 g, 0.007 mol) prepared in step 38-3 above (0.22 g, yield: 9.5%).

[0881] 1 H-NMR (400 MHz, DMSO-d 6): 9.92 (s, 1H), 9.24 (s, 1H), 8.90-8.89 (m, 1H), 8.61-8.59 (m, 3H), 8.52 (s, 1H), 7.93-7.88 (m, 1H), 7.64-7.61 (m, 1H), 1.69-1.64 (m, 1H), 0.56-0.53 (m, 2H), 0.20-0.16 (m, 2H).

[0882]

[0883] Step 38-5: Preparation of 1-(4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyrimidin-5-yl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0884] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyrimidin-5-yl)-1H-pyrrole-3-carbaldehyde (0.22 g, 0.001 mol) prepared in step 38-4 above (0.09 g, yield: 39.1%).

[0885] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.21 (s, 1H), 8.87-8.86 (dd, 1H), 8.64 (s, 1H), 8.61 (s, 1H), 8.55-8.54 (dd, 1H), 7.82-7.79 (m, 1H), 3.61 (s, 2H), 2.32 (s, 3H), 1.54 (m, 1H), 0.54-0.52 (m, 2H), 0.04-0.03(m, 2H).

[0886] [M+H] + : 370.32

[0887]

[0888] Example 39: Preparation of 1-(4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(quinoxalin-6-yl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0889]

[0890]

[0891] Step 39-1: Preparation of methyl 4-cyclopropyl-5-(quinoxalin-6-yl)-1H-pyrrole-3-carboxylate

[0892] The title compound was prepared in the same manner as in step 22-2 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.008 mol) and quinoxaline-6-boronic acid pinacol ester (2.52 g, 0.010 mol) prepared in step 1-3 above (1.45 g, yield: 60.4%).

[0893] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.94-8.90 (dd, 2H), 8.24 (s, 1H), 8.15-8.12 (m, 2H), 7.52-7.51 (d, 1H), 3.73 (s, 3H), 2.02-1.99 (m, 1H), 0.87-0.84 (m, 2H), 0.13-0.11 (m, 2H)

[0894]

[0895] Step 39-2: Preparation of methyl 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(quinoxalin-6-yl)-1H-pyrrole-3-carboxylate

[0896] The title compound was prepared in the same manner as in step 6-2 using methyl 4-cyclopropyl-5-(quinoxalin-6-yl)-1H-pyrrole-3-carboxylate (1.30 g, 0.004 mol) and pyridine-3-sulfonyl chloride (0.79 g, 0.004 mol) prepared in step 39-1 above. (1.69 g, yield: 87.6%)

[0897] 1 H-NMR (400 MHz, DMSO-d 6): 9.03-9.02 (d, 2H), 9.00-8.99 (d, 2H), 8.83-8.81 (dd, 1H), 8.45-8.44 (d, 1H), 8.15 (s, 1H), 8.07-8.05 (d, 1H), 7.89-7.86 (d, 1H), 7.70-7.69 (d, 1H), 7.59-7.50 (m, 2H), 3.61 (s, 3H), 1.81-1.77 (m, 1H), 0.45-0.43 (m, 2H), 0.13-0.11 (m, 2H)

[0898]

[0899] Step 39-3: Preparation of (4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(quinoxalin-6-yl)-1H-pyrrol-3-yl)methanol

[0900] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(quinoxalin-6-yl)-1H-pyrrole-3-carboxylate (1.5 g, 0.003 mol) prepared in step 39-2 above (1.20 g, yield: 85.7%).

[0901] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.04-8.96 (dd, 2H), 8.83-8.81 (dd, 1H), 8.45-8.44 (d, 1H), 8.08-8.05 (d, 1H), 7.85-7.73 (m, 2H), 7.64-7.62 (dd, 1H), 7.56-7.53 (m, 1H), 7.44 (s, 1H), 5.07 (br, 1H), 4.46-4.43 (d, 2H), 1.52-1.49 (m, 1H), 0.45-0.44 (m, 2H), 0.11-0.10 (m, 2H)

[0902]

[0903] Step 39-4: Preparation of 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(quinoxalin-6-yl)-1H-pyrrole-3-carbaldehyde

[0904] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(quinoxalin-6-yl)-1H-pyrrol-3-yl)methanol (1.20 g, 0.002 mol) prepared in step 39-3 above (0.68 g, yield: 87.1%).

[0905] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.96 (s, 1H), 9.10-9.00 (dd, 2H), 8.84-8.81 (dd, 1H), 8.52 (s, 1H), 8.47-8.46 (d, 1H), 8.08-8.06 (d, 1H), 7.87-7.85 (m, 1H), 7.71-7.70 (d, 1H), 7.59-7.45 (m, 2H), 1.72-1.70 (m, 1H), 0.50-0.48 (m, 2H), 0.06-0.05 (m, 2H)

[0906]

[0907] Step 39-5: Preparation of 1-(4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(quinoxalin-6-yl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0908] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(quinoxalin-6-yl)-1H-pyrrole-3-carbaldehyde (0.65 g, 0.002 mol) prepared in step 39-4 above (0.13 g, yield: 19.4%).

[0909] 1 H-NMR (400 MHz, DMSO-d 6): 9.02-8.97 (m, 2H), 8.82-8.81 (m, 1H), 8.45-8.44 (m, 1H), 8.08-8.06 (d, 1H), 7.79-7.74 (m, 2H), 7.65-7.63 (m, 1H), 7.55-7.54 (m, 1H), 7.44 (s, 1H), 3.56 (s, 2H), 2.30 (s, 3H), 1.56-1.50 (m, 1H), 0.46-0.42 (m, 2H), 0.06-0.00 (m, 2H).

[0910] [M+H] + : 420.03

[0911]

[0912] Example 40: Preparation of 1-(4-cyclopropyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0913]

[0914]

[0915] Step 40-1: Preparation of methyl 4-cyclopropyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-pyrrole-3-carboxylate

[0916] The title compound was prepared in the same manner as in step 22-2 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.008 mol) and 1,4-benzodioxane-6-boronic acid (1.74 g, 0.010 mol) prepared in step 1-3 above (1.80 g, yield: 74.7%).

[0917] 1 H-NMR (400 MHz, DMSO-d 6): 11.96 (s, 1H), 7.71 (s, 1H), 7.29-7.21 (m, 2H), 7.02-6.99 (m, 1H), 4.30-4.27 (m, 4H), 3.71 (s, 3H), 2.33-2.29 (m, 1H), 1.23-1.21 (m, 2H), 1.02-0.98 (m, 2H).

[0918]

[0919] Step 40-2: Preparation of methyl 4-cyclopropyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

[0920] The title compound was prepared in the same manner as in step 6-2 using methyl 4-cyclopropyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-pyrrole-3-carboxylate (1.80 g, 0.006 mol) and pyridine-3-sulfonyl chloride (1.17 g, 0.007 mol) prepared in step 40-1 above (2.30 g, yield: 86.8%).

[0921] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.86-8.84 (dd, 1H), 8.47-8.46 (d, 1H), 8.00 (s, 1H), 7.86-7.83 (m, 1H), 7.59-7.55 (m, 1H), 6.77-6.75 (d, 1H), 6.43-6.40 (dd, 1H), 6.33-6.32 (d, 1H), 4.30-4.24 (m, 4H), 3.77 (s, 3H), 1.76-1.74 (m, 1H), 0.48-0.46 (m, 2H), 0.15-0.13 (m, 2H).

[0922]

[0923] Step 40-3: Preparation of (4-cyclopropyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol

[0924] The title compound was prepared in the same manner as in step 1-6 using methyl 4-cyclopropyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (2.0 g, 0.005 mol) prepared in step 40-2 above (1.60 g, yield: 85.6%).

[0925] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.83-8.81 (dd, 1H), 8.44-8.43 (d, 1H), 7.77-7.74 (m, 1H), 7.58-7.56 (m, 1H), 7.29 (s, 1H), 6.79-6.77 (d, 1H), 6.47-6.41 (m, 2H), 4.98-4.96 (t, 1H), 4.37-4.36 (d, 2H), 4.28-4.25 (m, 4H), 1.41-1.36 (m, 1H), 0.47-0.44 (m, 2H), 0.21-0.18 (m, 2H)

[0926]

[0927] Step 40-4: Preparation of 4-cyclopropyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0928] The title compound was prepared in the same manner as in step 1-7 using (4-cyclopropyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol (1.50 g, 0.004 mol) prepared in step 40-3 above (0.88 g, yield: 59.1%).

[0929] 1 H-NMR (400 MHz, DMSO-d 6): 9.88 (s, 1H), 8.87-8.86 (dd, 1H), 8.49-8.48 (d, 1H), 8.38 (s, 1H), 7.87-7.84 (m, 1H), 7.61-7.58 (m, 1H), 6.79-6.77 (d, 1H), 6.44-6.41 (m, 1H), 6.34-6.33 (d, 1H), 4.30-4.24 (m, 4H), 1.67-1.65 (m, 1H), 0.53-0.51 (m, 2H), 0.35-0.33 (m, 2H)

[0930]

[0931] Step 40-5: Preparation of 1-(4-cyclopropyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0932] The title compound was prepared in the same manner as in step 1-8 using 4-cyclopropyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.88 g, 0.002 mol) prepared in step 40-4 above (0.6 g, yield: 65.9%).

[0933] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.82-8.81 (m, 1H), 8.44-8.43 (m, 1H), 7.77-7.74 (m, 1H), 7.58-7.56 (m, 1H), 7.29 (s, 1H), 6.79-6.77 (d, 1H), 6.46-6.42 (m 2H), 4.29-4.24 (m, 4H), 3.51 (s, 2H), 2.30 (s, 3H), 1.42-1.38 (m, 1H), 0.48-0.43 (m, 2H), 0.13-0.10 (m, 2H).

[0934] [M+H] + : 426.00

[0935]

[0936] Example 41: Preparation of 1-(5-(2-chlorophenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0937]

[0938]

[0939] Step 41-1: Preparation of methyl 5-(2-chlorophenyl)-4-cyclopropyl-1H-pyrrole-3-carboxylate

[0940] The title compound was prepared in the same manner as in step 1-4 using methyl 5-bromo-4-cyclopropyl-1H-pyrrole-3-carboxylate (0.030 mol) and 2-chlorophenylboronic acid (5.67 g, 0.036 mol) prepared in step 1-3 above (5.14 g, yield: 61.7%).

[0941] 1 H-NMR (400 MHz, DMSO-d 6 ): 11.43 (s, 1H), 7.55-7.53 (m, 1H), 7.43-7.37 (m, 4H), 3.69 (s, 3H), 1.91-1.84 (m, 1H), 0.53-0.50 (m, 2H), 0.06-0.02 (m, 2H).

[0942]

[0943] Step 41-2: Preparation of methyl 5-(2-chlorophenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

[0944] The title compound was prepared in the same manner as in step 1-5 using methyl 5-(2-chlorophenyl)-4-cyclopropyl-1H-pyrrole-3-carboxylate (5.14 g, 0.019 mol) and pyridine-3-sulfonyl chloride (4.97 g, 0.028 mol) prepared in step 41-1 above (7.34 g, yield: 94.5%).

[0945] 1 H-NMR (400 MHz, DMSO-d 6): 8.94-8.89 (dd, 1H), 8.51-5.46 (d, 1H), 8.12 (s, 1H), 7.96-7.93 (dq, 1H), 7.62-7.61 (m, 1H), 7.51-7.50 (m, 1H), 7.43-7.37 (m, 2H), 7.20-7.16 (dd, 1H), 3.79 (s, 3H), 1.77-1.73 (m, 1H), 0.50-0.41 (m, 2H), 0.14-0.06 (m, 2H).

[0946]

[0947] Step 41-3: Preparation of (5-(2-chlorophenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol

[0948] The title compound was prepared in the same manner as in step 1-6 using methyl 5-(2-chlorophenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (7.34 g, 0.018 mol) prepared in step 41-2 above (2.02 g, yield: 29.5%).

[0949] 1 H-NMR (400 MHz, DMSO-d 6 ): 8.88-8.85 (dd, 1H), 8.50-8.49 (d, 1H), 7.86-7.83 (m, 1H), 7.61-7.58 (m, 1H), 7.45-7.35 (m, 4H), 7.12-7.10 (m, 1H), 5.04-5.01 (t, 1H), 4.42-4.41 (d, 2H), 1.37-1.33 (m, 1H), 0.43-0.40 (m, 2H), 0.19-0.13 (m, 2H)

[0950]

[0951] Step 41-4: Preparation of 5-(2-chlorophenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

[0952] The title compound was prepared in the same manner as in step 1-7 using (5-(2-chlorophenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanol (2.02 g, 0.004 mol) prepared in step 41-3 above (1.37 g, yield: 68.2%).

[0953] 1 H-NMR (400 MHz, DMSO-d 6 ): 9.92 (s, 1H), 8.92-8.90 (dd, 1H), 8.52-8.51 (d, 1H), 8.49 (s, 1H), 7.94-7.91 (m, 1H), 7.64-7.60 (m, 1H), 7.55-7.50 (m, 1H), 7.45-7.36 (m, 2H), 7.20-7.17 (dd, 1H), 1.67-1.63 (m, 1H), 0.54-0.47 (m, 2H), 0.29-0.26 (m, 2H)

[0954]

[0955] Step 41-5: Preparation of 1-(5-(2-chlorophenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

[0956] The title compound was prepared in the same manner as in step 1-8 using 5-(2-chlorophenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (1.37 g, 0.004 mol) prepared in step 41-4 above (0.37 g, yield: 26.1%).

[0957] 1 H-NMR (400 MHz, DMSO-d 6): 8.88-8.85 (m, 1H), 8.52-8.50 (m, 1H), 7.86-7.82 (m, 1H), 7.61-7.60 (m, 1H), 7.47-7.33 (m, 4H), 7.10-7.08 (m, 1H), 3.65 (s, 2H), 2.38 (s, 3H), 1.39-1.37 (m, 1H), 0.41-0.40 (m, 2H), 0.11-0.06(m, 2H).

[0958] [M+H] + : 402.30

[0959]

[0960] Experimental Example 1: Preparation of gastric vesicles

[0961] The gastric vesicles used in the experiment were prepared from porcine stomach according to a published method (ab234055 ATPase Assay Kit-Colorimetric_Abcam, Version 1, 1 July 2019). The protein contents of the prepared gastric vesicles were analyzed by Pierce TM Quantification was performed using the BCA Protein Assay Kit (Thermo SCIENTIFIC).

[0962]

[0963] Experimental Example 2: Inhibitory activity on proton pump (H+ / K+-ATPase) activity

[0964] Proton pump (H) of the compound prepared in the above example + / K + The inhibitory activity on -ATPase activity was measured as follows (condition of final compound concentration of 1 μM).

[0965] 25 μL of a reaction solution containing gastrointestinal vesicles (40 mM Tris, 80 mM NaCl, 8 mM MgAc2, 1 mM EDTA, pH 7.5) was added to each well of a 96-well plate, and 5 μL of an 8 μM test compound (4% DMSO) and 10 μL of adenosine triphosphate (4 mM ATP) were added to each well, followed by enzyme reaction at 37°C for 30 minutes. 200 μL of malachite green solution was then added to stop the enzyme reaction at 25°C for 30 minutes. The amount of monophosphate (Pi) in the reaction solution was measured at 620 nm using a microplate reader (Tecan). The inhibition rate (%) was calculated from the activity value of the control group. The results are shown in Table 1 below.

[0966] [Table 1]

[0967]

[0968]

[0969] Experimental Example 3: Rat Efficacy Test

[0970] [Test compound]

[0971] The compound of Example 8 was mixed with 0.5% carboxymethyl cellulose at 0.1, 0.3, 1, 3, and 10 mg / kg / 5ml based on rat body weight.

[0972]

[0973] [Comparative Compound]

[0974] Comparative Example 1 was prepared by mixing tegoprazan in 0.5% carboxymethyl cellulose at 0.1, 0.3, 1, 3, and 10 mg / kg / 5ml based on rat body weight.

[0975] Comparative Example 2 was prepared by mixing esomeprazole in 0.5% carboxymethyl cellulose at 0.3, 1, 3, 10, and 30 mg / kg / 5ml based on rat body weight.

[0976]

[0977] [Experimental Method]

[0978] Gastric fluid volume, gastric acid secretion, and pH were measured through pyloric ligation, and changes in response to administration of test and comparative compounds were confirmed.

[0979] The experimental results were expressed as mean±SD, and statistical significance was tested using pairwise comparisons using the Wilcoxon rank-sum exact test, and the significance of each administration group was determined compared to the control group.

[0980] Six male SD rats weighing 250 g or more were divided into 16 groups, including Group 1, and fasted for 24 hours with free access to water. Then, the test compound (Example 8) and comparative compounds (Comparative Examples 1 and 2) were orally administered. One hour after administration of the test drug, pyloric ligation was performed, and three hours later, the stomach was removed to measure gastric fluid volume, electrolyte concentration, and pH. The results are shown in Table 2 below.

[0981] [Table 2]

[0982]

[0983]

[0984] As can be seen in Table 2 above, the 3 and 10 mg / kg administration groups of the compound of Example 8 showed significant differences compared to the control group in gastric juice volume, gastric acid secretion, and pH. In particular, there were significant differences in gastric acid secretion volume (p<0.005) and pH (p<0.01). The intermediate effective dose (ED 50 ) are compared, as shown in Table 3 below.

[0985] [Table 3]

[0986]

[0987]

[0988] It was confirmed that the intermediate effective dose of the compound of Example 8 was significantly lower than that of Comparative Example 1, which was the same P-CAB, and Comparative Example 2, which was a PPI.

Claims

A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, R 1 is aryl, partially unsaturated heterocyclyl or heteroaryl; wherein said aryl, partially unsaturated heterocyclyl and heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy, haloalkoxy, cycloalkoxy, cycloalkyl-alkoxy and heteroaryl; R 2 is aryl or heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy, haloalkyl and heteroaryl; The above partially unsaturated heterocyclyl and heteroaryl have one or more heteroatoms selected from N, O and S. In the first paragraph, R 1 Silver C6-C 10 Aryl, partially unsaturated 5 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl; wherein said aryl, partially unsaturated heterocyclyl and heteroaryl are halo, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, C3-C 10 Cycloalkoxy, C3-C 10 which may be optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl-C1-C7alkoxy and 5 to 12 membered heteroaryl; R 2 is C6-C 10 Aryl or 5 to 12 membered heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkyl and 5 to 12 membered heteroaryl; A compound or a pharmaceutically acceptable salt thereof, wherein the partially unsaturated heterocyclyl and heteroaryl have 1 to 3 heteroatoms selected from N, O and S. In the first paragraph, R 1 is C6 aryl, partially unsaturated 8 to 12 membered heterocyclyl or 5 to 12 membered heteroaryl; wherein said aryl, partially unsaturated heterocyclyl and heteroaryl may be optionally substituted with one or two substituents selected from the group consisting of halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkoxy, C3-C8 cycloalkoxy, C3-C8 cycloalkyl-C1-C5 alkoxy and 5 to 10 membered heteroaryl; A compound or a pharmaceutically acceptable salt thereof, wherein the partially unsaturated heterocyclyl and heteroaryl have 1 to 3 heteroatoms selected from N and O. In the first paragraph, R 2 is C6 aryl or 5 to 10 membered heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with 1 or 2 substituents selected from the group consisting of halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkyl and 5 to 10 membered heteroaryl; A compound or a pharmaceutically acceptable salt thereof, wherein the heteroaryl has 1 to 3 heteroatoms selected from N and O. In the first paragraph, R 1 is C6 aryl, partially unsaturated 9 or 10 membered heterocyclyl or 6 to 10 membered heteroaryl; wherein said aryl, partially unsaturated heterocyclyl and heteroaryl may be optionally substituted with one or two substituents selected from the group consisting of halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkoxy, C3-C8 cycloalkyl-C1-C5 alkoxy and 5 or 6 membered heteroaryl; A compound or a pharmaceutically acceptable salt thereof, wherein the partially unsaturated heterocyclyl and heteroaryl have one or two heteroatoms selected from N and O. In the first paragraph, R 2 is C6 aryl, or 5 or 6 membered heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with 1 or 2 substituents selected from the group consisting of halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkyl and 5 or 6 membered heteroaryl; A compound or a pharmaceutically acceptable salt thereof, wherein the heteroaryl has one or two heteroatoms selected from N and O. In claim 1, a compound characterized in that the chemical formula 1 is the following chemical formula 1-1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1-1] In the above chemical formula 1-1, R 2 is as defined in paragraph 1; R 3 and R 4 are each independently -H, halo, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, C3-C 10 Cycloalkoxy, C3-C 10 Cycloalkyl-C1-C7alkoxy or 5 to 12 membered heteroaryl; The above heteroaryl has 1 to 3 heteroatoms selected from N, O and S. In paragraph 7, R 3 and R 4 are each independently -H, halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkoxy, C3-C8 cycloalkyl-C1-C5 alkoxy, or 5 or 6 membered heteroaryl; A compound or a pharmaceutically acceptable salt thereof, wherein the heteroaryl has one or two heteroatoms selected from N and O. In paragraph 7, R 2 is C6 aryl, or 5 or 6 membered heteroaryl; wherein said aryl and heteroaryl may be optionally substituted with 1 or 2 substituents selected from the group consisting of halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkyl and 5 or 6 membered heteroaryl; A compound or a pharmaceutically acceptable salt thereof, wherein the heteroaryl has one or two heteroatoms selected from N and O. In the first paragraph, a compound characterized in that the chemical formula 1 is one selected from the following chemical formulas 1-2 to 1-8, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1-2] [Chemical Formula 1-3] [Chemical Formula 1-4] [Chemical Formula 1-5] [Chemical Formula 1-6] [Chemical Formula 1-7] [Chemical Formula 1-8] In the above chemical formulas 1-2 to 1-8, R 2 is as defined in paragraph 1; R 3 and R 4 are each independently -H, halo, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, C3-C 10 Cycloalkoxy, C3-C 10 Cycloalkyl-C1-C7alkoxy or 5 to 12 membered heteroaryl; The above heteroaryl has 1 to 3 heteroatoms selected from N, O and S. In Article 10, R 3 and R 4 are each independently -H, halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkoxy, C3-C8 cycloalkyl-C1-C5 alkoxy, or 5 or 6 membered heteroaryl; A compound or a pharmaceutically acceptable salt thereof, wherein the heteroaryl has one or two heteroatoms selected from N and O. A compound or a pharmaceutically acceptable salt thereof, characterized in that the pharmaceutically acceptable salt in claim 1 is hydrochloride, phosphate, fumarate, citrate, tartrate or succinate. In claim 1, a compound or a pharmaceutically acceptable salt thereof, characterized in that the compound represented by the chemical formula 1 is selected from the group consisting of the following compounds: 1) 1-(4-cyclopropyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 2) 1-(4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-phenyl-1H-pyrrol-3-yl)-N-methylmethanamine; 3) 1-(4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 4) 1-(4-cyclopropyl-1-((6-methylpyridin-3-yl)sulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 5) 1-(4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(o-tolyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 6) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 7) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride; 8) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine fumarate; 9) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine 2-hydroxypropane-1,2,3-tricarboxylate; 10) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine phosphate; 11) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine succinate; 12) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine 2,3-dihydroxysuccinate; 13) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methylpyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 14) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 15) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 16) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 17) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 18) 1-(4-cyclopropyl-5-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 19) 1-(1-((4-(1H-pyrazol-1-yl)phenyl)sulfonyl)-4-cyclopropyl-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 20) 1-(4-cyclopropyl-5-(4-fluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 21) 1-(5-(4-(1H-pyrrol-1-yl)phenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl-N-methylmethanamine; 22) 1-(4-cyclopropyl-5-(2-fluoro-4-(1H-pyrrol-1-yl)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 23) 1-(4-cyclopropyl-5-(4-(cyclopropylmethoxy)-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 24) 1-(4-cyclopropyl-5-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 25) 1-(4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 26) 1-(4-cyclopropyl-5-(2-fluoro-6-methoxyphenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 27) 1-(4-cyclopropyl-5-(2-fluoro-4-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 28) 1-(4-cyclopropyl-5-(2,4-difluorophenyl)1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 29) 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 30) 1-(4-Cyclopropyl-5-(2,4-difluorophenyl)-1-((6-methylpyridin-3-yl)-sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 31) 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl-1H-pyrrol-3-yl)-N-methylmethanamine; 32) 1-(4-cyclopropyl-5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride; 33) 1-(4-cyclopropyl-5-(2-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 34) 1-(4-cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-methoxyphenyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 35) 1-(4-Cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyridin-4-yl)-1H-pyrrol-3-yl)-N-methylmethanamine; 36) 1-(4-cyclopropyl-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; 37) 1-(4-Cyclopropyl-1-((3-fluorophenyl)sulfonyl)-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl)-N-methylmethanamine; 38) 1-(4-Cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(pyrimidin-5-yl)-1H-pyrrol-3-yl)-N-methylmethanamine; 39) 1-(4-Cyclopropyl-1-(pyridin-3-ylsulfonyl)-5-(quinoxalin-6-yl)-1H-pyrrol-3-yl)-N-methylmethanamine; 40) 1-(4-cyclopropyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; and 41) 1-(5-(2-Chlorophenyl)-4-cyclopropyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine. A pharmaceutical composition for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases, comprising a therapeutically effective amount of a compound represented by the chemical formula 1 according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 14, characterized in that the gastrointestinal inflammatory disease or gastric acid-related disease is gastrointestinal ulcer, gastritis or reflux esophagitis.

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