1-Heterocyclylsulfonyl, 3-aminomethyl, 5-(hetero-)aryl substituted 1-H-pyrrole derivatives as acid s

专利摘要:
Abstract The present invention provides a compound having a superior acid secretion inhibitory effect and showing an antiulcer activity and the like. The present invention provides a compound represented by the formula (1) wherein R' is a nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle, the nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s), R2 is an optionally substituted C6-14 aryl group, an optionally substituted thienyl group or an optionally substituted pyridyl group, R3 and R4 are each a hydrogen atom, or one of R3 and R4 is a hydrogen atom and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and R5 is an alkyl group or a salt thereof. 3990097 1 (GHMatters) P76750.AU.1
公开号:AU2013200142A1
申请号:U2013200142
申请日:2013-01-11
公开日:2013-03-07
发明作者:Atsushi Hasuoka；Masahiro Kajino；Haruyuki Nishida
申请人:Takeda Pharmaceutical Co Ltd；
IPC主号:C07D207-48

专利说明:
1-Heterocyclylsulfonyl, 3 -aminomethyl, 5- (hetero-) aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors Technical Field The present invention relates to pyrrole compounds having 5 an acid secretion suppressive activity. Background Art Proton pump inhibitors represented by omeprazole, which suppress secretion of gastric acid for the treatment of peptic ulcer, reflux esophagitis and the like, have been widely used lo in clinical situations. However, the existing proton pump inhibitors are associated with problems in terms of effect and side effects. To-be specific, since the existing proton pump ihhibitors are unstable under acidic conditions, they are often formulated as enteric preparations, in which case 15 several hours are required before expression of the effect. In addition, since the existing proton pump inhibitors show inconsistent treatment effects due to metabolic enzyme polymorphism and drug interaction with pharmaceutical agents such as diazepam and the like, an improvement has been 20 desired. As pyrrole compounds having a proton pump inhibitory action, EP-A-0259085 describes a compound represented by the formula: N 25 N' S N
CH
3
CH
6
CH
2 NH
NH
2 SO 2
C
6
H
5 and the like. As compounds having a thromboxane A2 (TXA2) antagonistic action and a TXA2 synthase inhibitory action, JP-A-8-119936 describes a compound represented by the formula: 30 r5 rI Ar4 r2 ZO wherein r1 is carboxy, protected carboxy, carboxy(lower)alkyl, protected carboxy(lower)alkyl, carboxy(lower)alkenyl or protected carboxy(lower)alkenyl, r2 is hydrogen; lower alkyl; 5 heterocyclic (lower)alkyl optionally having aminoimino or protected aminoimino; heterocyclic (lower)alkenyl; or heterocyclic carbonyl, r3 is hydrogen or lower alkyl, r4 is acyl, r5 is hydrogen, Ao is lower alkylene, and Zo is S or NH, provided when rl is carboxy or protected carboxy, then Zo is 10 NH. Moreover, as a therapeutic drug for neoplastic diseases or autoimmune diseases, W02004/103968 describes a compound represented by the formula: r8 15 r N SO2 r6 wherein r6 is aryl, aralkyl or heteroaryl, r7 is aryl or heteroaryl, and r8 is aryl, heteroaryl or optionally substituted aminomethyl. Disclosure of the Invention 20 Problems to be Solved by the Invention A pharmaceutical agent that effectively suppresses gastric acid secretion as known proton pump inhibitors, which is improved in instability under acidic conditions, dispersion of effects due to metabolic enzyme polymorphism and drug 25 interaction, which.are problems of known proton pump inhibitors, is expected to show more superior treatment effect 2 on peptic ulcer, reflux esophagitis and the like. As the situation stands, however, a proton pump inhibitor capable of sufficiently satisfying these requirements has not been found. It is therefore an object of the present invention to provide 5 a compound having a superior acid secretion suppressive effect (particularly, proton pump inhibitory effect), which has been improved in these problems. Means of Solving the Problems The present inventors have conducted various studies and 10 found that a compound represented by the formula (I): 3
H
2
/R
5 R C-N R2 N R4 22 R4 wherein R' is a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a 15 heterocycle, the monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s),
R
2 is an optionally substituted C 6
-
1 4 aryl group, an optionally substituted thienyl group or an optionally substituted pyridyl 20 group,
R
3 and R 4 are each a hydrogen atom, or one of R 3 and R 4 is a hydrogen atom and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and 25 R 5 is an alkyl group, or a salt thereof [hereinafter to be abbreviated as compound (I)] unexpectedly has a very strong acid secretion suppressive effect (proton pump inhibitory effect), and is fully satisfactory as a pharmaceutical agent, which resulted in the completion of the present invention. so Accordingly, the present invention relates to the 3 following. [11 A compound represented by the formula (I): 3 H 2 /R R C-N / H R2 N R(I) U2 R wherein R' is a monocyclic nitrogen-containing heterocyclic 5 group optionally condensed with a benzene ring or a heterocycle, the monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent (s), R 2 is an optionally substituted C 6
.
14 aryl group, an optionally substituted thienyl 10 group or an optionally substituted pyridyl group, R 3 and R 4 are each a hydrogen atom, or one of R 3 and R 4 is a hydrogen atom and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and R 5 is an alkyl group, or a salt thereof. 15 [21 A compound represented by the formula (I): 3 H2 /R R C-N I H 22 R wherein R 1 is a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, the monocyclic nitrogen-containing heterocyclic 20 group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s), R2 is an optionally substituted C6-14 aryl group or an optionally substituted thienyl group, R 3 and R 4 are each a hydrogen atom, or one of R 3 and R 4 is a hydrogen atom and the other is an optionally 25 substituted lower alkyl group, an acyl group, a halogen atom, 4 a cyano group or a nitro group, and R 5 is an alkyl group, or a salt thereof. [3] The compound of the above-mentioned [1] or [2], wherein R' is a monocyclic nitrogen-containing heterocyclic group. 5 [4] The compound of the above-mentioned [11 or [21, wherein the monocyclic nitrogen-containing heterocyclic group is a pyridyl group. [5] The compound of the above-mentioned [1] or [2], wherein R 2 is a phenyl group optionally substituted by 1 to 5 lo substituents selected from (i) a halogen atom and (ii) a C16 alkyl optionally substituted by 1 to 5 halogen atoms. [6] The compound of the above-mentioned [1) or [21, wherein R 2 is a pyridyl group optionally substituted by 1 to 4 substituent(s) selected from C-6 alkyl, a halogen atom, alkoxy, 15 cyano, acyl, nitro and amino. [71 The compound of the above-mentioned [1] or [2], wherein R 3 and R 4 are each a hydrogen atom. [8] The compound of the above-mentioned [1] or [2], wherein R 5 is a methyl group. 20 [9] 1-{5-(2-Fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyll 1H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof. [101 1-[4-Fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]-N-methylmethanamine or a salt thereof. [11] N-Methyl-i-[5-(4-methyl-3-thienyl)-1-(pyridin-3 25 ylsulfonyl)-lH-pyrrol-3-yllmethanamine or a salt thereof. [121 1-[5-(2-Fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-lH pyrrol-3-yl]-N-methylmethanamine or a salt thereof. [13]1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]-N-methylmethanamine or a salt thereof. 3o [14] N-Methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yllmethanamine or a salt thereof. [151 A prodrug of the compound of the above-mentioned [11 or [21. [16] A pharmaceutical composition comprising the compound of 35 the above-mentioned [1] or [2] or a prodrug thereof. 5 [17] The pharmaceutical composition of the above-mentioned [16], which is an acid secretion inhibitor. [18] The pharmaceutical composition of the above-mentioned [16], which is a potassium-competitive acid blocker. 5 [19] The pharmaceutical composition of the above-mentioned [16], which is an agent for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, 10 gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress. [20] A method of treating or preventing peptic ulcer, 15 Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or a method of inhibiting upper gastrointestinal hemorrhage due to 20 peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress, which comprises administering an effective amount of the compound of the above-mentioned [1] or [2] or a prodrug thereof to a mammal. [21] Use of the compound of the above-mentioned [1] or [2] or 25 a prodrug thereof for the production of a pharmaceutical composition for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric so cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress. Effect of the Invention 35 Since compound (I) shows a superior proton pump 6 inhibitory effect (while conventional proton pump inhibitors such as omeprazole, lansoprazole etc. form a covalent bond with a cysteine residue of H+/K+-ATPase and irreversibly inhibit the enzyme activity, since compound (I) inhibits the 5 proton pump (H+/K+-ATPase) activity reversibly and in a K+ antagonist inhibitory manner to consequently suppress acid secretion, it is sometimes referred to as a potassium competitive acid blocker: P-CAB or an acid pump antagonist (ACPA or APA)), it can provide a clinically useful 10 pharmaceutical composition for the prophylaxis and/or treatment of peptic ulcer (e.g., gastric ulcer, gastric ulcer due to postoperative stress, duodenal ulcer, anastomotic ulcer, ulcer caused by non-steroidal anti-inflammatory agents, ulcer due to postoperative stress etc.); Zollinger-Ellison 15 syndrome; gastritis; erosive esophagitis; reflux esophagitis such as erosive reflux esophagitis and the like; symptomatic gastroesophageal reflux disease (symptomatic GERD) such as non-erosive reflux disease or gastroesophageal reflux disease free of esophagitis and the like; functional dyspepsia; 20 gastric cancer (including gastric cancer associated with promoted production of interleukin-1p due to gene polymorphism of interleukin-1); stomach MALT lymphoma; gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, 25 hemorrhagic gastritis or invasive stress (e.g. stress caused by major surgery requiring postoperative intensive management, and cerebrovascular disorder, head trauma, multiple organ failure and extensive burn, each requiring intensive treatment) and the like. Furthermore, compound (I) is used for 3o the prophylaxis and/or treatment of airway disorders; asthma and the like, pre-anesthetic administration, eradication of Helicobacter pylori or eradication assistance and the like. Since compound (I) shows low toxicity and is superior in water-solubility, in vivo kinetics and efficacy expression, it 35 is useful as a pharmaceutical composition. Moreover, since 7 compound (I) is stable even under acidic conditions, which enables oral administration of the compound as a conventional tablet and the like without formulating an enteric-coated preparation. This has a consequence that the preparation of 5 tablet and the like can be made smaller, which is advantageous in that it is easily swallowed by patients having difficulty in swallowing, particularly the elderly and children. In addition, since a sustained release effect afforded by enteric-coated preparations is absent, expression of a gastric 10 acid secretion-suppressive action is rapid, and alleviation of symptoms such as pain and the like is rapid. -Best Mode for Embodying the Invention In the formula (I), as the "nitrogen-containing monocyclic heterocyclic group optionally condensed with a 15 benzene ring or a heterocycle" for R 1 , (1) a nitrogen-containing monocyclic heterocyclic group, and (2) a fused ring group represented by the formula: a A B b 20 wherein ring A is a nitrogen-containing monocyclic heterocyclic group, ring B is a benzene ring or a heterocycle, a and b are each a bridgehead ring-constituting atom (e.g., a carbon atom, a nitrogen atom and the.like), and = shows a single bond or a double bond, provided that a bond to an -SO 2 25 group in the formula (I) is present in a ring A-constituting atom (ring atom) other than the bridgehead ring-constituting atoms a and b, can be mentioned. As used herein, ring A needs only to contain, as a ring A-constituting atom (ring atom), at least one (preferably 1 to 30 4,' more preferably 1 or 2) nitrogen atom, and one or both of the bridgehead ring-constituting atoms a and b may be nitrogen atoms. 8 The "nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle" optionally has substituent(s), and the substituent(s) may be present in any of ring A and ring B. 5 As the "nitrogen-containing monocyclic heterocyclic group" of the "nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle" and the above-mentioned ring A, for example, an aromatic nitrogen-containing monocyclic heterocyclic group, a 10 saturated or unsaturated non-aromatic nitrogen-containing monocyclic heterocyclic group (aliphatic nitrogen-containing monocyclic heterocyclic group) and the like containing, as a ring-constituting atom (ring atom), at least one (preferably 1 to 4, more preferably 1 or 2) nitrogen atom can be mentioned. 15 As the "aromatic nitrogen-containing monocyclic heterocyclic group", for example, aromatic nitrogen-containing monocyclic heterocyclic groups such as pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl (lH-imidazol 1-yl, 1H-imidazol-4-yl etc.), pyrazolyl, 1,2,3-oxadiazolyl, 20 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3 thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3 triazolyl, 1,2,4-triazolyl (1,2,4-triazol-1-yl, 1,2,4-triazol 4-yl etc.), tetrazolyl, pyridyl (2-, 3- or 4-pyridyl etc.), pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, 25 and N-oxide forms thereof and the like can be mentioned. Of these, a 5- or 6-membered aromatic nitrogen-containing monocyclic heterocyclic group is preferable, and thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl and pyridazinyl are preferable, and pyridyl is particularly preferable. 30 As the "saturated or unsaturated non-aromatic nitrogen containing monocyclic heterocyclic group", partially reduced forms (e.g., imidazolinyl, tetrahydropyrimidinyl and the like) of the above-mentioned "aromatic nitrogen-containing monocyclic heterocyclic group" and, for example, azetidinyl, 35 pyrrolidinyl, piperidyl (2-, 3- or 4-piperidyl), morpholinyl, 9 thiomorpholinyl, piperazinyl (1-piperazinyl etc.), homopiperazinyl and the like can be mentioned. Of these, a 5 or 6-membered non-aromatic nitrogen-containing monocyclic heterocyclic group is preferable. 5 As the "heterocycle" optionally condensed with a nitrogen-containing monocyclic heterocyclic group, for example, an aromatic heterocycle or non-aromatic heterocycle can be mentioned. As the "aromatic heterocycle", for example, 5- or 6 10 membered aromatic heteromonocyclic rings such as a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, an imidazole ring, a pyrazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,3,4-oxadiazole ring, a furazan 15 ring, a 1,2,3-thiadiazole ring, a 1,2,4-thiadiazole ring, a 1,3,4-thiadiazole ring, a 1,2,3-triazole ring, a 1,2,4 triazole ring, tetrazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring and the like and, for example, 8- to 12-membered aromatic fused 20 heterocycles such as a benzofuran ring, an isobenzofuran ring, a benzo[b]thiophene ring, an indole ring, an isoindole ring, a 1H-indazole ring, a benzindazole ring, a benzoxazole ring, a 1,2-benzoisoxazole ring, a benzothiazole ring, a benzopyran ring, a 1,2-benzoisothiazole ring, a 1H-benzotriazole ring, a 25 quinoline ring, an isoquinoline ring, a cinnoline ring, a quinazoline ring, a quinoxaline ring, a phthalazine ring, a naphthyridine ring, a purine ring, a pteridine ring, a carbazole ring, an c-carboline ring, a p-carboline ring, a carboline ring, an acridine ring, a phenoxazine ring, a 30 phenothiazine ring, a phenazine ring, a phenoxathiine ring, a thianthrene ring, a phenanthridine ring, a phenanthrone ring, an indolizine ring, a pyrrolo[1,2-blpyridazine ring, a py'razolo[1,5-alpyridine ring, an imidazo[1,2-alpyridine ring, an imidazo[1,5-alpyridine ring, an imidazo[1,2-b]pyridazine 35 ring, an imidazo[1,2-a]pyrimidine ring, a 1,2,4-triazolo[4,3 10 a]pyridine ring, a 1,2,4-triazolo[4,3-b]pyridazine ring and the like (preferably, a heterocycle wherein the aforementioned 5- or 6-membered aromatic heteromonocyclic ring is condensed with a benzene ring or a heterocycle wherein the same or 5 different two heterocycles of the aforementioned 5- or 6 membered aromatic heteromonocyclic ring are condensed, more preferably a heterocycle wherein the aforementioned 5- or 6 membered aromatic monocyclic heterocyclic group is condensed with a benzene ring, preferably imidazopyrimidinyl etc.) and 10 the like can be mentioned. As the "non-aromatic heterocycle", for example, 3- to 8 membered saturated or unsaturated non-aromatic heterocycles such as an oxirane ring, an azetidine ring, an oxetane ring, a thietane ring, a pyrrolidine ring, a tetrahydrofuran ring, a 15 thioran ring, a piperidine ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a piperazine ring, a 3-hexahydrocyclopenta[clpyrrole ring, a homopiperidine ring, a homopiperazine ring and the like, or non-aromatic heterocycles wherein the double bonds of the aforementioned aromatic 20 heteromonocyclic ring or aromatic fused heterocycle are partly or entirely saturated such as a dihydropyridine ring, a dihydropyrimidine ring, a 1,2,3,4-tetrahydroquinoline ring, a 1,2,3,4-tetrahydroisoquinoline ring and the like, and the like can be mentioned. 25 As preferable nitrogen-containing monocyclic heterocyclic group condensed with a benzene ring or a heterocycle, for example, nitrogen-containing aromatic fused heterocyclic groups such as 8- to 16-membered (preferably 8- to 12 membered) nitrogen-containing aromatic bicyclic fused 30 heterocyclic groups such as 2- or 3-indolyl, 1- or 3 isoindolyl, 1H-indazol-3-yl, 2-benzimidazolyl, 2-benzoxazolyl, 3-benzoisoxazolyl, 2-benzothiazolyl, 3-benzoisothiazolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl, 3- or 4-cinnolinyl, 2- or 4-quinazolinyl, 2- or 3-quinoxalinyl, 1- or 4 35 phthalazinyl, naphthyridinyl, purinyl, pteridinyl, 1,7 11 phenanthrolin-2-, 3- or 4 -yl, 1-, 2- or 3-indolizinyl, pyrrolo[1,2-b]pyridazinyl,. pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,2-b]pyrazolyl, imidazo[1,5 a]pyridyl, imidazo[4,5-c]pyridyl, pyrazolo[1,5-a]pyrimidinyl, 5 pyrazolo[1,5-c]pyrimidinyl, pyrazolo[3,4-dlpyrimidinyl, imidazo[1,2-blpyridazinyl, imidazo[1,5-b]pyridazinyl, pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyrimidinyl, 1,2,4 triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-blpyridazinyl, [1,2,4]triazolo[1,2-a]pyridazinyl, [1,2,3]triazolo[1,5 lo alpyrimidinyl, [1,2,4]triazolo[l,5-c]pyrimidinyl, [1,2,4]triazolo[1,5-alpyridyl, [1,2,4]triazolo[4,3-a]pyridyl, pyrazolo[5,1-b]thiazolyl, pyrrolo[2,1-f][1,2,4]triazinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[2,3-dipyrimidinyl, pyrrolo[2,3-b]pyridyl, thieno[3,2-b]pyrimidinyl, thieno[2,3 25 b]pyridyl, thieno[2,3-c]pyridyl, thieno[3,2-b]pyridyl, thieno[3,2-clpyridyl, pyrido[2,3-blpyrazyl, pyrido[3,4 b]pyrazyl, pyrido[2,3-dipyrimidinyl, pyrido[3,2-d:pyrimidinyl, pyrido[4,3-d]pyrimidinyl and the like, and the like, and the like can be mentioned. As the nitrogen-containing aromatic 20 fused heterocycle, fused pyridine wherein a pyridine ring is condensed with one or two (preferably one) of the aforementioned 5- or 6-membered nitrogen-containing aromatic monocyclic heterocycles or one or two (preferably one) benzene rings (when condensed with a benzene ring, the pyridine ring 25 has a bond), fused pyrimidine wherein a pyrimidine ring is condensed with one or two (preferably one) of the aforementioned 5 or 6-membered nitrogen-containing aromatic monocyclic heterocycles, or one or two (preferably one) benzene rings (when condensed with a benzene ring, the 30 pyrimidine ring has a bond) and the like are preferable. As the " non-aromatic nitrogen-containing heterocycle", for example, 3- to 8-membered (preferably 5- or 6-membered) ni'trogen-containing saturated or unsaturated (preferably saturated) non-aromatic heterocycle (aliphatic nitrogen 35 containing heterocycle) such as azetidine, pyrrolidine, 12 imidazolidine, thiazolidine, oxazolidine, piperidine, morpholine, thiomorpholine, piperazine and the like, or nitrogen-containing non-aromatic heterocycle wherein the double bonds of the aforementioned nitrogen-containing 5 aromatic monocyclic heterocycle or nitrogen-containing aromatic fused heterocycle are partly or entirely saturated, such as 1,2,3,4-tetrahydroquinoline, 1,2,3,4 tetrahydroisoquinoline and the like, and the like can be mentioned. 10 As the "nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle", a 5- or 6-membered aromatic nitrogen-containing monocyclic heterocyclic group is preferable from among those mentioned above. Of them, a 6-membered aromatic nitrogen-containing 15 heterocyclic group such as pyridyl (e.g., 2-, 3- or 4-pyridyl etc.), pyrimidinyl (e.g., 2-, 4- or 5-pyrimidinyl etc.), pyridazinyl (e.g., 3- or 4-pyridazinyl etc.) and the like is preferable, and pyridyl is particularly preferable. As the substituent that the "nitrogen-containing 20 monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle" may have, (1) a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom etc.), (2) nitro, (3) cyano, (4) hydroxy, (5) C1_ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec 25 butoxy, pentyloxy, hexyloxy, fluoromethoxy etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (6) C-14 aryloxy (e.g., phenyloxy, naphthyloxy etc.), (7) C 7
-
1 6 aralkyloxy (e.g., benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy, 2 30 naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy, 4 phenylbutyloxy, 5-phenylpentyloxy etc.), (8) mercapto, (9) C1_ alkylthio (e.g., methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio 35 etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, 13 chlorine, bromine, iodine), (10) C6-14 arylthio (e.g., phenylthio, naphthylthio etc.), (11) C7-16 aralkylthio (e.g., benzylthio, phenethylthio, diphenylmethylthio, 1 naphthylmethylthio, 2-naphthylmethylthio, 2,2 5 diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 5 phenylpentylthio etc.), (12) amino, (13) mono-C- 6 alkylamino (e.g., methylamino, ethylamino etc.), (14) mono-C 6
-
1 4 arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino etc.), (15) mono-C 7
-
1 6 aralkylamino (e.g., benzylamino etc.), (16) di 10 C1-6 alkylamino (e.g., dimethylamino, diethylamino etc.), (17) di-C 6
-
1 4 arylamino (e.g., diphenylamino etc.), (18) di-C 7 1 6 aralkylamino (e.g., dibenzylamino etc.), (19) formyl, (20) C1-6 alkyl-carbonyl (e.g., acetyl, propionyl etc.), (21) C6-14 aryl carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.), (22) 15 carboxyl, (23) C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.), (24) C 6
-
1 4 aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), (25) carbamoyl, (26) thiocarbamoyl, (27) mono-C 1
-
6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.), (28) di-Ci 20 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), (29) C6-14 aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), (30) C1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (31) C6-14 arylsulfonyl (e.g., 25 phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl etc.), (32) C1.6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.), (33) C6-14 arylsulfinyl (e.g., phenylsulfinyl, 1 naphthylsulfinyl, 2-naphthylsulfinyl etc.), (34) formylamino, (35) C1-6 alkyl-carbonylamino (e.g., acetylamino etc.), (36) CC 30 14 aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37) C1-6 alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino etc.), (38) Ci16 alkylsulfonylamino (e.g., methylsulfonylamino, 35 ethylsulfonylamino etc.), (39) C-14 arylsulfonylamino (e.g., 14 phenylsulfonylamino, 2-naphthylsulfonylamino, 1 naphthylsulfonylamino etc.), (40) C 1
-
6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.), (41) C6-14 aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy etc.), (42) C-6 alkoxy 5 carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy etc.), (43) mono-C- 6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.), (44) di-Ci- 6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy etc.), (45) C6i 4 10 aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to 7-membered saturated cyclic amino (e.g., pyrrolidin-1-yl, piperidino, piperazin-1 yl, morpholino, thiomorpholino, hexahydroazepin-1-yl etc.) optionally containing, besides one nitrogen atom and carbon 15 atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3 thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3 quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 20 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2 indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3 benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.) containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an 25 oxygen atom, (48) C1,3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), (49) C3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.), (50) C1-6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 30 isopentyl, neopentyl, n-hexyl, isohexyl etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (51) a C2-6 alkenyl group (e.g., allyl, isopropenyl, isobutenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, 35 chlorine, bromine, iodine), (52) a C2-6 alkynyl group (e.g., 15 propargyl, 2-butynyl, 3-butynyl, 3-pentynyl, 3-hexynyl etc.), (53) a C1-6 alkyl group (e.g., hydroxymethyl, hydroxyethyl etc.) substituted by 1 to 3 hydroxy and the like can be mentioned. The substituent may be present at a substitutable 5 position, and the number of the substituents is 1 to 5, preferably 1 to 3. As the "C6-1 4 aryl group" of the "optionally substituted C6-14 aryl group" for R 2 , for example, phenyl, 1-naphthyl, 2 naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl 10 and the like can be mentioned. As the substituent that the "C6-14 aryl group" optionally has, groups similar to the substituents. that the "nitrogen containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle" for the aforementioned R, 15 optionally has can be mentioned. The number of the substituents is 1 to 5, preferably 1 to 3. As the "thienyl group" of the "optionally substituted thienyl group" for R 2 , 2- or 3-thienyl can be mentioned. 20 As the substituent that the "thienyl group" optionally has, groups similar to the substituents that the "nitrogen containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle" for the aforementioned R' optionally has can be mentioned. 25 The number of the substituents is 1 to 4, preferably 1 to 3. As the "pyridyl group" of the "optionally substituted pyridyl group" for R 2 , 2-, 3- or 4-pyridyl, or bipyridyl (e.g., 2,3'-bipyridin-5-yl) can be mentioned. 30 As the substituent that the "pyridyl group" optionally has, groups similar to the substituents that the "nitrogen containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle" for the aforementioned R 1 optionally has can be mentioned. 35 The number of the substituents is 1 to 4, preferably 1 to 16 3. As the "lower alkyl group" of the "optionally substituted lower alkyl group" for R 3 or R 4 , for example, Ci-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5 sec-butyl, tert-butyl and the like, and the like can be mentioned. As the substituent that the "lower alkyl group" optionally has, (1) a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom etc.), (2) nitro, (3) 20 cyano, (4) hydroxy, (5) Ci-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, fluoromethoxy etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (6) C6-14 aryloxy (e.g., phenyloxy, naphthyloxy etc.), (7) C7-16 15 aralkyloxy (e.g., benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy, 2,2 diphenylethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy, 5 phenylpentyloxy etc.), (8) mercapto, (9) C1-6 alkylthio (e.g., methylthio, difluoromethylthio, trifluoromethylthio, 20 ethylthio, propylthio, isopropylthio, butylthio, 4,4,4 trifluorobutylthio, pentylthio, hexylthio etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (10) C6-14 arylthio (e.g., phenylthio, naphthylthio etc.), (11) C7-16 aralkylthio (e.g., benzylthio, 25 phenethylthio, diphenylmethylthio, 1-naphthylmethylthio, 2 naphthylmethylthio, 2,2-diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentylthio etc.) (12) amino, (13) mono-CI- 6 alkylamino (e.g., methylamino, ethylamino etc.), (14) mono-C 6 s 1 4 arylamino (e.g., phenylamino, 1-naphthylamino, 2 30 naphthylamino etc.), (15) mono-C 7
-.
6 aralkylamino (e.g., benzylamino etc.), (16) di-Ci- 6 alkylamino (e.g., dimethylamino, diethylamino etc.), (17) di-C.
1 4 arylamino (e.g., diphenylamino etc.), (18) di-C 7
-
1 6 aralkylamino (e.g., dibenzylamino etc.), (19) formyl, (20) C- alkyl-carbonyl (e.g., acetyl, propionyl 35 etc.), (21) C6-14 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2 17 naphthoyl etc.), (22) carboxyl, (23) Ci-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert butoxycarbonyl etc.), (24) CG.14 aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), (25) carbamoyl, (26) thiocarbamoyl, 5 (27) mono-C.-6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.), (28) di-C- 6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), (29) C-14 aryl-carbamoyl (e.g., phenylcarbamoyl, 1 naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), (30) Ci-6 10 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (31) C6-14 arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2 naphthylsulfonyl etc.), (32) C1-6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.), (33) C6-14 arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl 15 etc.), (34) formylamino, (35) C1-6 alkyl-carbonylamino (e.g., acetylamino etc.), (36) C-14 aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37) C1-6 alkoxy carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino 20 etc.), (38) CI-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino etc.), (39) C6-14 arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino, 1 naphthylsulfonylamino etc.), (40) Ci-6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.), (41) C6-14 aryl-carbonyloxy (e.g., 25 benzoyloxy, naphthylcarbonyloxy etc.), (42) C-6 alkoxy carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy etc.), (43) mono-Ci- 6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.), (44) di-C- 6 alkyl-carbamoyloxy (e.g., 3o dimethylcarbanoyloxy, diethylcarbamoyloxy etc.), (45) C6-14 aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected s from a nitrogen atom, a sulfur atom and an oxygen atom (e.g., 18 pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl etc.), (47) a 5- to 10 membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from 5 a nitrogen atom, a sulfur atom and an oxygen atom (e.g., 2 thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1 isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1 indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2 10 benzo[bithienyl, 3-benzo[b]thienyl, 2-benzo[bifuranyl, 3 benzo[b]furanyl etc.), (48) C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), and (49) C3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.) and the like can be mentioned. 15 The number of the substituents is 1 to 3. As the "acyl group" for R 3 or R 4 , an acyl group having 1 to 20 carbon atoms, which is derived from organic carboxylic acid can be mentioned. For example, Ci-7 alkanoyl groups (e.g., formyl; Ci-6 alkyl-carbonyl such as acetyl, propionyl, butyryl, 20 isobutyryl, pentanoyl, hexanoyl, heptanoyl and the like; etc.), CG.14 aryl-carbonyl groups (e.g., benzoyl, naphthalenecarbonyl etc.), Ci-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec 25 butoxycarbonyl, tert-butoxycarbonyl etc.), C6-14 aryloxy carbonyl groups (e.g., phenoxycarbonyl group), C7-19 aralkyl carbonyl groups (e.g., phenyl-C- 4 alkylcarbonyl such as benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl and the like, naphthyl-Ci- 4 alkylcarbonyl such as 3o benzhydrylcarbonyl, naphthylethylcarbonyl and the like, etc.), C7-19 aralkyloxy-carbonyl groups (e.g., phenyl-C..
4 alkyloxycarbonyl such as benzyloxycarbonyl and the like, etc.), 5- or 6-membered heterocycle-carbonyl group or condensed heterocycle-carbonyl groups thereof (e.g., 35 pyrrolylcarbonyl such as 2- or 3-pyrrolylcarbonyl and the 19 like; pyrazolylcarbonyl such as 3-, 4- or 5-pyrazolylcarbonyl and the like; imidazolylcarbonyl such as 2-, 4- or 5 imidazolylcarbonyl and the like; triazolylcarbonyl such as 1,2,3-triazol-4-ylcarbonyl, 1,2,4-triazol-3-ylcarbonyl and the 5 like; tetrazolylcarbonyl such as 1H- or 2H-tetrazol-5 ylcarbonyl and the like; furylcarbonyl such as 2- or 3 furylcarbonyl and the like; thienylcarbonyl such as 2- or 3 thienylcarbonyl and the like; oxazolylcarbonyl such as 2-, 4 or 5-oxazolylcarbonyl and the like; isoxazolylcarbonyl such as 10 3-, 4- or 5-isoxazolylcarbonyl and the like; oxadiazolylcarbonyl such as 1,2,3-oxadiazol-4- or 5 ylcarbonyl, 1,2,4-oxadiazol-3- or 5-ylcarbonyl, 1,2,5 oxadiazol-3- or 4-ylcarbonyl, 1,3,4-oxadiazol-2-ylcarbonyl and the like; thiazolylcarbonyl such as 2-, 4- or 5 25 thiazolylcarbonyl and the like; isothiazolylcarbonyl such as 3-, 4- or 5-isothiazolylcarbonyl and the like; thiadiazolylcarbonyl such as 1,2,3-thiadiazol-4- or 5 ylcarbonyl, 1,2,4-thiadiazol-3- or 5-ylcarbonyl, 1,2,5 thiadiazol-3- or 4-ylcarbonyl, 1,3,4-thiadiazol-2-ylcarbonyl 20 and the like; pyrrolidinylcarbonyl such as 2- or 3 pyrrolidinylcarbonyl and the like; pyridylcarbonyl such as 2-, 3- or 4-pyridylcarbonyl and the like; pyridylcarbonyl wherein nitrogen atom is oxidized such as 2-, 3- or 4-pyridyl-N oxidocarbonyl and the like; pyridazinylcarbonyl such as 3- or 25 4-pyridazinylcarbonyl and the like;.pyridazinyl wherein one or both nitrogen atoms are oxidized, such as 3-, 4-, 5- or 6 pyridazinyl-N-oxidocarbonyl and the like; pyrimidinylcarbonyl such as 2-, 4- or 5-pyrimidinylcarbonyl and the like; pyrimidinylcarbonyl wherein one or both nitrogen atoms are 30 oxidized, such as 2-, 4-, 5- or 6-pyrimidinyl-N-oxidocarbonyl and the like; pyrazinylcarbonyl; piperidinylcarbonyl such as 2-, 3- or 4-piperidinylcarbonyl and the like; piperazinylcarbonyl; indolylcarbonyl such as 3H-indol-2- or 3 ylcarbonyl and the like; pyranylcarbonyl such as 2-, 3- or 4 35 pyranylcarbonyl and the like; thiopyranylcarbonyl such as 2-, 20 3- or 4-thiopyranylcarbonyl and the like; quinolylcarbonyl such as 3-, 4-, 5-, 6-, 7- or 8-quinolylcarbonyl and the like; isoquinolylcarbonyl; pyrido[2,3-dlpyrimidinylcarbonyl (e.g., pyrido[2,3-d]pyrimidin-2-ylcarbonyl); naphthyridinylcarbonyl 5 (e.g., 1,5-naphthyridin-2- or 3-ylcarbonyl) such as 1,5-, 1,6 , 1,7-, 1,8-, 2,6- or 2,7-naphthyridinylcarbonyl and the like; thieno[2,3-dipyridylcarbonyl (e.g., thieno[2,3-d]pyridin-3 ylcarbonyl); pyrazinoquinolylcarbonyl (e.g., pyrazino[2,3 b]quinolin-2-ylcarbonyl); a 5- or 6-membered heterocycle 10 carbonyl group (e.g., chromenylcarbonyl (e.g., 2H-chromen-2 or 3-ylcarbonyl etc.) and the like) containing 1 to 4 hetero atoms such as nitrogen atom (optionally oxidized), oxygen atom, sulfur atom (optionally mono or dioxidized) and the like), a 5- or 6-membered heterocycle-acetyl group (e.g., 5 15 or 6-membered heterocycle-acetyl group containing 1 to 4 hetero atoms such as nitrogen atom (optionally oxidized), oxygen atom, sulfur atom (optionally mono or dioxidized) and the like), such as 2-pyrrolylacetyl, 3-imidazolylacetyl, 5 isoxazolylacetyl and the like, and the like can be used. 20 As regards the substituent of acyl group, for example, when the above-mentioned acyl group is an alkanoyl group or alkoxy-carbonyl group, the acyl group is optionally substituted by 1 to 3 alkylthio groups (e.g., Ci- 4 alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio and 25 the like, and the like), halogen (e.g., fluorine, chlorine, bromine, iodine), alkoxy groups (e.g., C1- alkoxy such as methoxy, ethoxy, n-propoxy, tert-butoxy, n-hexyloxy and the like, and the like), a nitro group, alkoxy-carbonyl groups (e.g., C1-6 alkoxy-carbonyl such as methoxycarbonyl, 30 ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert butoxycarbonyl and the like, and the like), alkylamino group (e'.g., mono- or di-C 1
-
6 alkylamino such as methylamino, ethylamino, n-propylamino, n-butylamino, tert-butylamino, n 3s pentylamino, n-hexylamino, dimethylamino, diethylamino, 21 methylethylamino, di-(n-propyl)amino, di-(n-butyl)amino and the like, and the like), alkoxyimino groups (e.g., C 1
-
6 alkoxyimino such as methoxyimino, ethoxyimino, n-propoxyimino, tert-butoxyimino, n-hexyloxy-imino and the like, and the like) 5 or hydroxyimino. When the above-mentioned acyl group is an aryl-carbonyl group, an aryloxy-carbonyl group, an aralkyl-carbonyl group, an aralkyloxycarbonyl group, a 5- or 6-membered heterocycle carbonyl group or a 5- or 6-membered heterocycle-acetyl group, 10 it is optionally substituted by 1 to 5 (preferably 1 to 3) alkyl groups (e.g., C1_ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and the like, C3- 6 cycloalkyl such as cyclohexyl and the like, and the 15 like), alkenyl groups (e.g., C 2 -6 alkenyl such as allyl, isopropenyl, isobutenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl and the like, and the like), alkynyl groups (e.g., C2-6 alkynyl such as propargyl, 2-butynyl, 3-butynyl, 3-pentynyl, 3-hexynyl and the like, and the like), alkoxy groups (e.g., C1-6 alkoxy 20 such as methoxy, ethoxy, n-propoxy, tert-butoxy, n-hexyloxy and the like, and the like), acyl groups [e.g., C1-7 alkanoyl such as formyl, acetyl, propionyl, butyryl,. isobutyryl, pentanoyl, hexanoyl, heptanoyl and the like; C-14 aryl-carbonyl such as benzoyl, naphthalenecarbonyl and the like; Cj-G alkoxy 25 carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like; C6-14 aryloxy-carbonyl such as phenoxycarbonyl and the like; C7-19 aralkyl-carbonyl such as phenyl-Ci- 4 alkyl-carbonyl 30 (e.g., benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl and the like) and the like; C7-19 aralkyloxy-carbonyl such as phenyl-Ci- 4 alkyloxy-carbonyl (e.g., benzyloxycarbonyl and the like) and the like, and the like], nitro, amino, hydroxy, cyano, sulfamoyl, mercapto, halogen (e.g., fluorine, chlorine, 35 bromine, iodine), or alkylthio groups (C1-4 alkylthio such as 22 methylthio, ethylthio, n-propylthio, isobutylthio and the like, and the like) As the "halogen atom" for R 3 or R 4 , fluorine, chlorine, bromine and iodine can be mentioned. 5 As the "alkyl group" for R 5 , for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, tert-butyl, pentyl, hexyl etc.) and the like can be mentioned. As R 1 , a "nitrogen-containing monocyclic heterocyclic 20 group optionally condensed with a benzene ring or a heterocycle" (e.g., 5-6-membered aromatic nitrogen-containing monocyclic heterocyclic groups such as thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like, and the like) optionally substituted by 1 to 3 15 substituents selected from (i) halogen (e.g., fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C16 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen 20 (e.g., fluorine, chlorine, bromine, iodine), (v) C1_6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (vi) amino group 25 optionally substituted by C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.), (vii) oxo and (viii) C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert butoxycarbonyl etc.) is preferable. 30 As R1, especially, a "nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle" (e.g., a 5-6-membered aromatic nitrogen containing monocyclic heterocyclic group such as thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, 35 pyrazinyl and the like, and the like), which is optionally 23 substituted by 1 to 3 substituents selected from (i) halogen (e.g., fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C3,6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 5 hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., 10 fluorine, chlorine, bromine, iodine), (vi) an amino group optionally substituted by C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) and (vii) oxo, is preferable. As R 1 , particularly, a 6-membered nitrogen-containing 15 aromatic heterocyclic group (e.g., pyridyl groups (e.g., 2-, 3- or 4-pyridyl etc.), pyrimidinyl groups (e.g., 2-, 4- or 5 pyrimidinyl etc.), pyridazinyl groups (e.g., 3- or 4 pyridazinyl etc.) etc.) optionally substituted by 1 to 3 substituents selected from (i) halogen (e.g., fluorine, 20 chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C16 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) C.6 alkoxy 25 (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) and (vi) an amino group optionally substituted by C-6 alkyl (e.g., methyl, ethyl, 30 propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) is preferable, and a pyridyl group optionally substituted by 1 to 3 substituents selected from (i') C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) 35 optionally substituted by 1 to 5 (preferably 1 to 3) halogen 24 (e.g., fluorine, chlorine, bromine, iodine) and (ii) Ces alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., 5 fluorine, chlorine, bromine, iodine) is particularly preferable. As R 2 , [1] a C-14 aryl group (e.g., phenyl group) optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom (e.g., fluorine, 10 chlorine, bromine, iodine), (ii) cyano, (iii) C16 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) C-6 alkoxy (e.g., methoxy, ethoxy, 15 propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) acetyl, (vi) C3- 7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.), (vii) C1 20 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (viii) a C16 alkyl group substituted by 1 to 3 hydroxy (e.g., hydroxymethyl, hydroxyethyl etc.), (ix) C1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, pentylthio, hexylthio etc.) 25 optionally substituted by 1 to 5 (preferably 1 to 3) halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and (x) C16 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.), [2] a thienyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., fluorine, 30 chlorine, bromine, iodine), (ii) cyano, (iii) C.6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) C1-6 alkoxy (e.g., methoxy, ethoxy, 35 propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, 25 hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) and (v) acetyl, or [3] a pyridyl group optionally substituted by 1 to 4 5 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) lower (specifically C1-6) alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to lo 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) Ci-5 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) acyl (e.g., acetyl), 15 (vi) nitro and (vii) amino is preferable. Of these, as R 2 , [11 a C-14 aryl group (e.g., phenyl group) optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C1.6 alkyl (e.g., 20 methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, 25 hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) and (v) acetyl, [2] a thienyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., fluorine, 3o chlorine, bromine, iodine), (ii) cyano, (iii) C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 '(preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) C-6 alkoxy (e.g., methoxy, ethoxy, 35 propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, 26 hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) and (v) acetyl, or [3] a pyridyl group optionally substituted by 1 to 4 5 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) lower (specifically C 1
-
6 ) alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to l0 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv)
C
1
-
6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g.,. fluorine, chlorine, bromine, iodine), (v) acyl (e.g., acetyl), 15 (vi) nitro and (vii) amino is preferable. Particularly, [1] a phenyl group optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and (ii) C 1
-
6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, 20 isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), [2] a thienyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., fluorine, 25 chlorine, bromine, iodine) and (ii) C 1
-
6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), or 30 [3] a pyridyl group optionally substituted by 1 to 4 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and (ii) lower (specifically C 1
.
6 ) alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) 35 optionally substituted by 1 to 5 (preferably 1 to 3) halogen 27 (e.g., fluorine, chlorine, bromine, iodine) is preferable. Of those mentioned above, a preferable embodiment of R 2 include [1] a phenyl group optionally substituted by 1 to 5 substituents selected from (i) a halogen atom and (ii) C1_6 5 alkyl optionally substituted by 1 to 5 halogen atoms, [2] a pyridyl group optionally substituted by 1 to 4 substituents selected from lower (C1-6) alkyl, a halogen atom, alkoxy (C-6 alkoxy), cyano, acyl (e.g., acetyl), nitro and amino, and the like. 10 As R 2 , a phenyl group, a 2-fluorophenyl group, a 2 methylphenyl group, a 2-fluoropyridin-3-yl group, a 3 fluoropyridin-4-yl group, a 2-chloropyridin-3-yl group, a 6 chloropyridin-3-yl group, a 4-methylpyridin-3-yl group, a 2 methylpyridin-3-yl group, a 3-methylpyridin-2-yl group, a 2 15 trifluoromethylpyridin-3-yl group and a 6'-chloro-2,3' bipyridin-5-yl group are particularly preferable. Preferably R and R4 are each a hydrogen atom, or one of R and R4 is a hydrogen atom and the other is a C1-6 alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl etc.), a CjG alkyl 20 carbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl etc.), a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a cyano group or a nitro group. A compound wherein both R3 and R4 are hydrogen atoms is particularly preferable. 25 As R5, methyl or ethyl is preferable, and methyl is particularly preferable. The above-mentioned preferable embodiments of the substituents for R' to R5 may be optionally combined to achieve a preferable embodiment of compound (I). 30 Of compounds (I), a compound wherein
R
1 is a 5-6-membered aromatic nitrogen-containing monocyclic heterocyclic group (for example, thiazolyl, imidazolyl, py'razolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like) or an imidazo[1,2-a]pyrimidinyl group, which are 35 optionally substituted by 1 to 3 substituents selected from 28 (i) halogen (e.g., fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C 1
-
6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) C1s alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), lo (vi) amino group optionally substituted by C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) and (vii) C1- alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert butoxycarbonyl etc.); 15 R2 is [1] a C1-14 aryl group (e.g., phenyl group) optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert 20 butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) C-e6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 25 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) acetyl, (vi) C3- 7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.), (vii) C1.6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (viii) a C 1
-
6 alkyl group substituted by 1 to 3 hydroxy (e.g., 3o hydroxymethyl, hydroxyethyl etc.), (ix) C 1
-
6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, pentylthio, hexylthio etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and (x) C16 35 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.), 29 [2] a thienyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 5 tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) C1- 6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 10 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) and (v) acetyl, [3] a pyridyl group optionally substituted by 1 to 4 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) lower 15 (specifically Ci-..) alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, 20 isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) acyl (e.g., acetyl), (vi) nitro and (vii) amino, or [41 a bipyridyl group optionally substituted by 1 to 3 halogen 25 atoms (e.g., fluorine, chlorine, bromine, iodine);
R
3 and R 4 are each a hydrogen atom, or one of R 3 and R4 is a hydrogen atom and the other is a Cje alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl etc.), a C 1 6 alkyl-carbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, 3o hexanoyl, heptanoyl etc.), a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a cyano group or a nitro group;
R
5 is methyl or ethyl is preferable, a compound wherein, for example R is a pyridyl group optionally substituted by 1 to 3 35 substituents selected from (i) C1-6 alkyl (e.g., methyl, ethyl, 30 propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) and (ii) Ci-6 alkoxy (e.g., methoxy, ethoxy, 5 propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), R2 is [1] a phenyl group optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen 10 atom (e.g., fluorine, chlorine, bromine, iodine) and (ii) C 1 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), 15 [2] a thienyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and (ii) C-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 20 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), or [3] a pyridyl group optionally substituted by 1 to 4 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and (ii) lower (specifically C16) 25 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine),
R
3 and R 4 are each a hydrogen atom, and R 5 is methyl is 30 particularly preferable. As compound (I), N-methyl-i-[5-phenyl-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]methanamine, 1-[5-(2-fluorophenyl) 1- (pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, N-methyl-i-[4-methyl-i-(pyridin-3-ylsulfonyl)-5-phenyl-lH 35 pyrrol-3-yl]methaneamine, N-methyl-1-[1-(pyridin-3 31 ylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanamine,
N
methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yllmethanamine, 1-[5-(2,4-difluorophenyl)-1-(pyridin 3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, 1-{5-(2 5 fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3 yl}-N-methylmethanamine, 1-[4-fluoro-5-phenyl-i-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, N-methyl-1 [5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol-3 yl]methanamine, 1-[5-(2-fluoropyridin-3-yl)-1-(pyridin-3 1o ylsulfonyl)-iH-pyrrol-3-yl]-N-methylmethanamine or a salt thereof is particularly preferable. As a salt of compound (I), metal salt, ammonium salt, salts with organic bases, salts with inorganic bases, salts with organic acids, salts with basic or acidic amino acids and 15 the like can be mentioned. Preferable examples of metal salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like. Preferable examples of the salt with organic base 20 include a salt with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N' dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include a salt with hydrochloric 25 acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, 30 malic acid, methanesulfonic acid, benzenesulfonic acid, p toluenesulfonic acid and the like. Preferable examples of the salt with basic amino acid include a salt with arginine, ly'sin, ornithine and the like. Preferable examples of the salt with acidic amino acid include a salt with aspartic acid, 35 glutamic acid and the like. 32 Of these, pharmaceutically acceptable salts are preferable. For example, when a compound contains an acidic functional group, inorganic salts such as alkali metal salt (e.g., sodium salt, potassium salt etc.), alkaline earth metal 5 salt (e.g., calcium salt, magnesium salt, barium salt etc.) and the like, ammonium salt and the like; and when a compound contains a basic functional group, for example, salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, or 20 salts with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. Compound (I) can be produced, for example, according to 15 the methods described in JP application No. 2005-044740, Eur. J. Org. Chem., p. 2283 (2001), J. Med. Chem., vol. 43, p. 1886 (2000), J. Pharm. Pharmacol., vol. 46, p. 740 (1994), W092/04025, J. Heterocycl. Chem., vol. 25, p. 635 (1988), J. Med. Chem., vol. 14, p. 328 (1971), J. Med. Chem., vol. 35, p. 20 4195 (1992) or Tetrahedron Lett., vol. 26, p. 4047 (1985), or a method analogous thereto. The production methods of compound (I) in the present invention are explained. The compounds (II)-(XXIV) in the formula may form salts, 25 and as such salts, for example, those similar to the salts of compound (I) can be mentioned. While the compounds obtained in respective steps can be used for the next reaction in the form of a reaction mixture or a crude product, they can also be easily isolated and 30 purified from the reaction mixture by a known separation and purification means, such as recrystallization, distillation, chromatography and the like. 33 0 RS OR, (Ilia) R4
R
3 OR O O 0 01) 0 (Villa) Ra OR Ra ORe R 3 OR or R 2 R NBS Olla) (Villb) H R 4 Br N Br N R 4 H I O= =o V) M MI 3 OHv R reduct ion R2 oxidation R R R / k- ~ 2 N Re Fe N W 4
R
2 N R4 o=T- =o- o=7o=0= RR R" . (X) (X) (la) Compound (II) wherein R 2 , R 3 and R 4 are as defined above, and R5 is a C 1 .4 alkyl group such as methyl, ethyl, propyl, 5 isopropyl, butyl and the like can be produced according to a method known per se, such as the method described in Chem. Pharm. Bull., vol. 49, p. 1406 (2001), Tetrahedron Letters, vol. 35, p. 5989 (1994) and the like or a method analogous thereto. 10 By reacting compound (II) with a compound represented by the formula (IIIa) R i-- I R 1 S-Ci 0 (Ilia) wherein R" is as defined for R', or the protecting group 15 described in Protective Groups in Organic Synthesis, 3 rd Ed. Theodora W. Greene, Peter G. M. Wuts, pp. 615-617, Wiley Interscience (1999) (e.g., phenyl, 4-methylphenyl etc.), compound (IV) (each symbol in the formula is as defined above) can be produced. 34 This reaction is advantageously carried out using a solvent inert to the reaction. While the solvent is not particularly limited as long as the reaction proceeds, hydrocarbons such as benzene, toluene and the like and ethers 5 such as tetrahydrofuran and the like, amides such as N,N dimethylformamide, N,N-dimethylacetamide and the like, and the like or a mixed solvent thereof and the like are preferable. Use of a base is effective for the reaction. As the base, for example, inorganic bases such as sodium hydride, 10 sodium hydroxide, potassium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate and the like, metal bases such as potassium ethoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide and the like, aromatic amines such 15 as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N methylmorpholine and the like, and the like can be mentioned. 20 The amount of the base to be used is about 1 - about 10 mol, preferably about 1 - about 5 mol, per 1 mol of compound (II). The reaction can also be carried out in the co-presence of crown ether. As the crown ether, for example, 15-crown-5 ether, 18-crown-6-ether and the like can be mentioned. The 25 amount of the crown ether to be used is about 1 - about 10 mol, preferably about 1 - about 5 mol, per 1 mol of compound (II). While the reaction time varies depending on the reagents and solvent to be used, it is generally about 30 min - about so 24 hr, preferably about 30 min - about 8 hr. The reaction temperature is generally about 00C - about 100oC, preferably about 100C - about 500C. Compound (V) (each symbol in the formula is as defined above) can be produced according to a method known per se, for 35 example, the methods described in Tetrahedron Letters, vol. 35 13, p. 5337 (1972), Heterocycles, vol. 7, p. 77 (1977), Chem. Pharm. Bull., vol. 27, p. 2857 (1979), J. Org. Chem., vol. 62, p. 2649 (1997) and the like, or a method analogous thereto. Compound (VI) (each symbol in the formula is as defined 5 above) can be produced by reacting compound (V) with N bromosuccinimide (NBS). N-Bromosuccinimide (NBS) is preferably used in about one equivalent amount relative to compound (V), and the reaction is preferably carried out under an inert gas atmosphere such 10 as nitrogen, argon and the like. This reaction is advantageously carried out using a solvent inert to the reaction. While the solvent is not particularly limited as long as the reaction proceeds, solvents such as ethers (e.g., tetrahydrofuran, diethyl ether 15 and the like), amides (e.g., N,N-dimethylformamide, N,N dimethylacetamide and the like) and the like, a mixed solvent thereof and the like are preferable. While the reaction time varies depending on the reagents and solvent to be used, it is generally about 30 min - about 20 24 hr, preferably about 5-12 hr. The reaction temperature is generally about -780C to about 250C, preferably about -780C to about 00C. Addition of a base is sometimes effective for the reaction. While the base to be used is not limited as long as 25 the reaction proceeds, an organic base such as pyridine, picoline, lutidine and the like, and the like can be mentioned. The amount of the organic base to be used is about 0.001 - about 10 equivalents, preferably about 0.001 - about 0.1 equivalent, per 1 mol of compound (V). 30 Compound (VII) (each symbol in the formula is as defined above) can be produced from compound (VI) according to a method similar to the method for producing compound (IV) from compound (II). Compound (IV) (each symbol in the formula is as defined 35 above) can also be produced by reacting compound (VII) with a 36 compound represented by the formula (VIIIa): OH R2 B OH (Villa) or the formula (VIIIb): 5 Me 0 2 / Me O -Me Me (Villb) wherein R 2 is as defined above, according to the method described in Synthetic Communications, vol. 11, p. 513 (1981), or a method analogous thereto. 10 Compound (IX) (each symbol in the formula is as defined above) can be produced by reducing compound (IV) with a reducing agent such as lithium aluminum hydride, diisobutyl aluminum hydride, sodium borohydride, calcium borohydride and the like. As the reducing agent, diisobutyl aluminum hydride 25 is particularly preferable. The amount of the reducing agent to be used is about 0.75 - about 10 equivalents, preferably about 1 - about 5 equivalents, per 1 mol of compound (IV). This reaction is advantageously carried out using a solvent inert to the reaction. While the solvent is not 20 particularly limited as long as the reaction proceeds, solvents such as hydrocarbons (e.g., benzene, toluene and the like) and ethers (e.g., tetrahydrofuran, diethyl ether and the like), and the like, a mixed solvent thereof and the like are preferable. 25 While the reaction time varies depending on the reagents and solvent to be used, it is generally about 30 min - about 24' hr, preferably about 30 min - about 8 hr. The reaction temperature is generally about -78 0 C to about 100 0 C, preferably about -78 0 C to about 25 0 C. 37 Compound (X) (each symbol in the formula is as defined above) can be synthesized by reacting compound (IX) with an oxidant such as chromic acid-pyridine complex, pyridinium chlorochromate, manganese dioxide, sulfur trioxide-pyridine 5 complex or tetra-n-propylammonium perruthenate and the like. As the oxidant, manganese dioxide, sulfur trioxide-pyridine complex or tetra-n-propylammonium perruthenate is preferable. The oxidation reaction can be carried out, for example, according to the method described in Synthesis, p. 639 (1994). 10 Compound (Ia) (each symbol in the formula is as defined above) can be produced by subjecting compound (X) and a compound represented by the formula (XI):
R--NH
2 15 wherein R 5 is as defined above, to a reductive amination reaction according to the methods described in Shin Jikken Kagaku Koza, Vol. 14-III, pp. 1380-1385 (Maruzen Press). In addition, compound (Ia) can also be produced by the following method. 20 38 0
ROR
6 R OH O / 4 r o 4 oxidation ( , Br N R 4 Beductionr N R BT N o=s=o o=s=o o=s=o IIl Il R R (VI) (x ) (xvo / R eiiai N protection of /roH aiino group gro Br N Fe Br N K4R 2 N o~s~oO~so0Osso R RR RR elimination of H protective group . Il (la) Compound (XII) (each symbol in the formula is as defined above) can be produced from compound (VII) according to a method similar to the method for producing compound (IX) from 5 compound (IV). Compound (XIII) (each symbol in the formula is as defined above) can be produced from compound (XII) according to a method similar to the method for producing compound (X) from compound (IX) . 10 Compound (XIV) (each symbol in the formula is as defined above) can be produced from compound (XIII) according to a method similar to the method for producing compound (Ia) from compound (X). Compound (XV) (each symbol in the formula is as defined 15 above and R' is an amino-protecting group) can be produced by protecting an amino group of compound (XIV) . As the amino protecting group, tert-butylcarbamate group (BOC group), benzylcarbamate group (Cbz group) and the like can be mentioned. The protection reaction can be carried out 39 according to a method known per se, for example, the method described in Protective Groups in Organic Synthesis, 3 rd Ed., Theodora W. Greene, Peter G. M. Wuts, pp. 494-653, Wiley Interscience (1999) and the like. 5 Compound (XVI) (each symbol in the formula is as defined above) can be produced from compound (XV) according to a method similar to the method for producing compound (IV) from compound (VII). Compound (Ia) (each symbol in the formula is as defined 20 above) can be produced by eliminating the amino-protecting group from compound (XVI) by a method known per se, for example, the method described in Protective Groups in Organic Synthesis, 3rd Ed., Theodora W. Greene, Peter G. M. Wuts, pp. 494-653, Wiley-Interscience (1999) and the like. 15 In addition, compounds (XVI) and (Ia) can also be produced by the following methods. 0 R ORreduction R R oxidation 4O ) R2R RN
R
2 2 R 2 / R0 R 2 ~ (Il) (XVil) (XVIll) (XIX)
RR
6 /R prtcin/f3F / R6elimination R prtcio fR) ~ of protective amino gro p R 7 (ilia) R R _ group R 2 Fe N R'RZ N o=s=o O=s=O (XX) 11 R (XVI) (la) Compound (XVII) (each symbol in the formula is as defined 20 above) can be produced from compound (II) according to a method similar to the method for producing compound (IX) from compound (IV) . Compound (XVIII) (each symbol in the formula is as defined above) can be produced from compound (XVII) according 25 to a method similar to the method for producing compound (X) from compound (IX). 40 Compound (XIX) (each symbol in the formula is as defined above) can be produced from compound (XVIII) according to a method similar to the method for producing compound (Ia) from compound (X). 5 Compound (XX) (each symbol in the formula is as defined above) can be produced from compound (XIX) according to a method similar to the method for producing compound (XV) from compound (XIV). Compound (XVI) (each symbol in the formula is as defined 10 above) can be produced from compound (XX) according to a method similar to the method for producing compound (IV) from compound (II) . Furthermore, compound (Ia) can be produced by a method similar to the aforementioned method. In addition, compounds (XIII), (X) and (Ia) can also be 15 produced by the following methods. 0 0 6W R 3 K OH oxidation R SO (ilila) H reduction OH d H R H N He N FeH N 4 ==oo-s-o o=s=o MR R R (XX I( D (XXIll NBS B Villa) (Vllb) / R (ll)R N RR2 N R o=s~o o=s~o R O-0 (W) 1 R2 R4 (Xvpi Compound (XXI) (each symbol in the formula is as defined 20 above) can be produced from compound (V) according to a method similar to the method for producing compound (IV) from 41 compound (II) . Compound (XXII) (each symbol in the formula is as defined above) can be produced from compound (XXI) according to a method similar to the method for producing compound (IX) from 5 compound (IV) . Compound (XXIII) (each symbol in the formula is as defined above) can be produced from compound (XXII) according to a method similar to the method for producing compound (X) from compound (IX). 10 Compound (XIII) (each symbol in the formula is as defined above) can be produced from compound (XXIII) according to a method similar to the method for producing compound (VI) from compound (V). Compound (X) (each symbol in the formula is as defined 15 above) can be produced from compound (XIII) according to a method similar to the method for producing compound (IV) from compound (VII), or from compound (XVIII) according to a method similar to the method for producing compound (IV) from compound (II). Furthermore, compound (Ia) can be produced 20 according to a method similar to the aforementioned method. Moreover, compound (XIII) and compound (XVIII) can also be synthesized by the following method, and compound (Ia) can be further produced by a method similar to the aforementioned method. 25 R 3 -0 (Illa) BR/RS B N fRe
-R
2 N R (villa) (Xl ) Br or 3 .o i , /WN (Vilib) (X R 4O (a) H 42 Compound (XXIV) (each symbol in the formula is as defined above) can be produced according to a method known per se, for example, the method described in J. Org. Chem., vol. 55, p. 6317 (1990) and the like, or a method analogous thereto. 5 Compound (XIII) (each symbol in the formula is as defined above) can be produced from compound (XXIV) according to a method similar to the method for producing compound (IV) from compound (II). Compound (XVIII) (each symbol in the formula is as 10 defined above) can be produced from compound (XXIV) according to a method similar to the method for producing compound (IV) from compound (VII). When R" is a group other than the group represented by R' in each compound, the compound can be converted to compound 15 (I) after deprotection by a method known per se, for example, the method described in Protective Groups in Organic Synthesis, 3rd Ed., Theodora W. Greene, Peter G. M. Wuts, pp. 615-617, Wiley-Interscience (1999) and the like, using the formula (III) 20 0 iI
R
1 -S-C1 11 0 wherein each symbol in the formula is as defined above, according to a method similar to the method for producing compound (IV) from compound (II). 25 In each of the aforementioned reactions, when the starting compound has an amino group, a carboxyl group or a hydroxy group as a substituent, a protecting group generally used in peptide chemistry and the like may be introduced into these groups. In this case, by eliminating the protecting 30 group as necessary after the reaction, the objective compound can be obtained. Introduction and elimination of these protecting groups can be performed by a method known per se, 43 for example, the method described in Protective Groups in Organic Synthesis, 3rd Ed., Theodora W. Greene, Peter G. M. Wuts, Wiley-Interscience (1999) and the like. Compound (I) can be isolated and purified by a known 5 means such as phase transfer, concentration, solvent extraction, fractionation, liquid conversion, crystallization, recrystallization, chromatography and the like. When compound (I) is obtained as a free compound, it can be converted to a desired salt by a method known per se or a lo method analogous thereto; conversely, when compound (I) is obtained as a salt, it can be converted into a free form or another desired salt by a method known per se or a method analogous thereto. Compound (I) may be used as a prodrug. The prodrug of 15 compound (I) means a compound which is converted to compound (I) under the physiological condition in the body by a reaction with an enzyme, gastric acid, or the like, that is, a compound which is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, and the like; a compound 20 which is converted to compound (I) by hydrolysis with gastric acid, and the like. The prodrug of compound (I) includes a compound wherein the amino group of compound (I) is modified with acyl, alkyl or phosphoryl (e.g., a compound wherein the amino group of 25 compound (I) is modified with eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4 yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl or t-butyl, etc.); a compound wherein the hydroxy group of compound (I) is modified with acyl, alkyl, 30 phosphoric acid or boric acid (e.g., a compound wherein the hydroxy group of compound (I) is modified with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl or dimethylaminomethylcarbonyl, etc.); a compound wherein a carboxyl group of compound (I) is modified to ester or amide 35 (e.g., a compound wherein a carboxyl group of compound (I) is 44' modified to ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2 oxo-1,3-dioxolen-4-yl)methyl ester, cyclohexyloxycarbonylethyl 5 ester or methylamide, etc.); and the like. These prodrugs can be produced from compound (I) by a method known per se. In addition, the prodrug of compound (I) may be a compound, which is converted to compound (I) under the physiological conditions, as described in Pharmaceutical 10 Research and Development, Vol. 7 (Molecule Design), pp. 163 198 (1990), published by Hirokawa Publishing Co. When compound (I) contains an optical isomer, a stereoisomer, a regioisomer or a rotamer, either isomer and a mixture of these are also encompassed in compound (I). For 15 example, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I). These isomers can be obtained as single products according to synthesis and separation methods known per se (concentration, solvent extraction, column chromatography, 20 recrystallization, etc.). The compound (I) may be a crystal, and both a single crystal and crystal mixtures are encompassed in compound (I). Crystals can be produced by crystallization according to crystallization methods known per se. 25 The compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate, both of which are encompassed in the compound (I). A compound labeled with an isotope (e.g., 3 H, 14 C, 35 , 1251 and the like) is also encompassed in the compound (I). 30 Compound (I) and a prodrug thereof of the present invention (hereinafter sometimes to be abbreviated as the compound of the present invention) have a proton pump inhibitory effect and effectively suppress gastric acid secretion. In addition, since they show low toxicity (e.g., 35 acute toxicity, chronic toxicity, genetic toxicity, 45 reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity and the like) and high water-solubility, and are superior in the stability, in vivo kinetics (absorbability, distribution, metabolism, excretion and the 5 like), and efficacy expression, they are useful as pharmaceutical agents. The compound of the present invention is useful for the treatment or prophylaxis of peptic ulcer (e.g., gastric ulcer, gastric ulcer due to postoperative stress, duodenal ulcer, lo anastomotic ulcer, ulcer caused by non-steroidal anti inflammatory agents etc.); Zollinger-Ellison syndrome; gastritis; erosive esophagitis; reflux esophagitis such as erosive reflux esophagitis and the like; symptomatic gastroesophageal reflux disease (symptomatic GERD) such as 15 non-erosive reflux disease or gastroesophageal reflux disease free of esophagitis and the like; functional dyspepsia; gastric cancer (including gastric cancer associated with promoted production of interleukin-lp due to gene polymorphism of interleukin-1); stomach MALT lymphoma; gastric 20 hyperacidity; upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress (e.g. stress caused by major surgery requiring postoperative intensive management, and cerebrovascular disorder, head trauma, multiple organ failure and extensive 25 burn, each requiring intensive treatment) and the like; airway disorders; asthma and the like, pre-anesthetic administration, eradication of Helicobacter pylori or eradication assistance and the like, in mammals (e.g., human, simian, sheep, cattle, horse, dog, cat, rabbit, rat, mouse etc.). 30 As used herein, the above-mentioned reflux esophagitis and symptomatic gastroesophageal reflux disease (symptomatic GERD)) are sometimes collectively referred to simply as GERD. The content of a compound of the present invention in the pharmaceutical composition of the present invention is about 35 0.01 to 100% by weight relative to the entire composition. 46 Though subject to change depending on the administration target, administration route, target disease and the like, its dose is about 0.5 to 1,500 mg/day, preferably about 5 to 150 mg/day, based on the active ingredient, when, for example, the 5 compound is orally administered as an anti-ulcer agent to an adult human (60 kg). The compound of the present invention may be administered once daily or in 2 or 3 divided portions per day. The compound of the present invention shows low toxicity lo and can be appropriately administered orally or parenterally (e.g., topical, rectal, intravenous administrations and the like) as it is or as a preparation containing a pharmaceutical composition containing a pharmacologically acceptable carrier admixed according to a method known per se, such as tablets 15 (including sugar-coated tablets and film-coated tablets), powder, granule, capsule (including soft capsule), orally disintegrating tablet, orally disintegrating film, liquid, injection, suppository, sustained-release preparation, plaster and the like. Particularly, the compound of the present 20 invention is preferably administered as an oral preparation in the form of tablet, granule, capsule and the like. The pharmacologically acceptable carrier that may be used to produce the pharmaceutical composition of the present invention includes various organic or inorganic carrier 25 substances in common use as pharmaceutical materials, including excipients, lubricants, binders, disintegrants, water-soluble polymers and basic inorganic salts for solid preparations; and solvents, dissolution aids, suspending agents, isotonizing agents, buffers and soothing agents for 3o liquid preparations and the like. Other ordinary pharmaceutical additives such as preservatives, anti-oxidants, coloring agents, sweetening agents, souring agents, bubbling agents and flavorings may also be used as necessary. Such "excipients" include, for example, lactose, sucrose, 35 D-mannitol, starch, cornstarch, crystalline cellulose, light 47 silicic anhydride, titanium oxide and the like. Such "lubricants" include, for example, magnesium stearate, sucrose fatty acid esters, polyethylene glycol, talc, stearic acid and the like. 5 Such "binders" include, for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, crystalline cellulose, starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, low-substituted hydroxypropyl cellulose and the like. 10 Such "disintegrants" include (1) crosspovidone, (2) what is called super-disintegrants such as crosscarmellose sodium (EWC-Asahi Chemical) and carmellose calcium (Gotoku Yakuhin) etc, (3) carboxymethyl starch sodium (e.g., product of Matsutani Chemical), (4) low-substituted hydroxypropyl 15 cellulose (e.g., product of Shin-Etsu Chemical), (5) corn starch, and so forth. Said "crosspovidone" may be any crosslinked polymer having the chemical name 1-ethenyl-2 pyrrolidinone homopolymer, including polyvinylpyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone homopolymer, and is 20 exemplified by Colidon CL (produced by BASF), Polyplasdon XL (produced by ISP), Polyplasdon XL-10 (produced by ISP), Polyplasdon INF-10 (produced by ISP) and the like. Such "water-soluble polymers" include, for example, ethanol-soluble water-soluble polymers [e.g., cellulose 25 derivatives such as hydroxypropyl cellulose (hereinafter also referred to as HPC) etc, polyvinylpyrrolidone and the like], ethanol-insoluble water-soluble polymers [e.g., cellulose derivatives such as hydroxypropylmethyl cellulose (hereinafter also referred to as HPMC) etc., methyl cellulose, 30 carboxymethyl cellulose sodium and the like, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like] and the like. Such "basic inorganic salts" include, for example, basic inorganic salts of sodium, potassium, magnesium and/or 35 calcium. Preferred are basic inorganic salts of magnesium 48 and/or calcium. More preferred are basic inorganic salts of magnesium. Such basic inorganic salts of sodium include, for example, sodium carbonate, sodium hydrogencarbonate, disodium hydrogenphosphate and the like. Such basic inorganic salts of 5 potassium include, for example, potassium carbonate, potassium hydrogencarbonate and the like. Such basic inorganic salts of magnesium include, for example, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium aluminometasilicate, magnesium silicate, magnesium 10 aluminate, synthetic hydrotalcite [MgAl 2
(OH)
1 6 -CO3-4H 2 01, and aluminum magnesium hydroxide. Preferred are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like. Such basic inorganic salts of calcium include, for example, precipitated calcium carbonate, calcium 15 hydroxide, etc. Such "solvents" include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Such "dissolution aids" include, for example, 20 polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Such "suspending agents" include, for example, 25 surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate etc; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl 30 cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose etc., and the like. Such "isotonizing agents" include, for example, glucose, D-sorbitol, sodium chloride, glycerol, D-mannitol and the like. 35 Such "buffers" include, for example, buffer solutions of 49 phosphates, acetates, carbonates, citrates etc, and the like. Such "soothing agents" include, for example, benzyl alcohol and the like. Such "preservatives" include, for example, p-oxybenzoic 5 acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Such "antioxidants" include, for example, sulfites, ascorbic acid, a-tocopherol and the like. Such "coloring agents" include, for example, food colors lo such as Food Color Yellow No. 5, Food Color Red No. 2, Food Color Blue No. 2 etc.; food lake colors, red oxide and the like. Such "sweetening agents" include, for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, 25 thaumatin and the like. Such "souring agents" include, for example, citric acid (citric anhydride), tartaric acid, malic acid and the like. Such "bubbling agents" include, for example, sodium bicarbonate and the like. 20 Such "flavorings" may be synthetic substances or naturally occurring substances, and include, for example, lemon, lime, orange, menthol, strawberry and the like. The compound of the present invention may be prepared as a preparation for oral administration in accordance with a 25 commonly-known method, by, for example, compression-shaping with a carrier such as an excipient, a disintegrant, a binder, a lubricant, or the like, and subsequently coating the preparation as necessary by a commonly known method for the purpose of taste masking, enteric dissolution or sustained 30 release. For an enteric preparation, an intermediate layer may be provided by a commonly known method between the enteric layer and the drug-containing layer for the purpose of separation of the two layers. For preparing the compound of the present invention as an 35 orally disintegrating tablet, available methods include, for 50 example, a method in which a core containing crystalline cellulose and lactose is coated with the compound of the present invention and, where necessary, a basic inorganic salt, and then further coated with a coating layer containing 5 a water-soluble polymer to give a composition, which is coated with an enteric coating layer containing polyethylene glycol, further coated with an enteric coating layer containing triethyl citrate, still further coated with an enteric coating layer containing polyethylene glycol, and finally coated with 10 mannitol to give fine granules, which are mixed with additives and shaped. The above-mentioned "enteric coating layer" includes, for example, a layer consisting of a mixture of one or more kinds from aqueous enteric polymer substrates such as cellulose 15 acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, methacrylic acid copolymers (e.g., Eudragit L30D-55 (trade name; produced by Rohm), Colicoat MAE30DP (trade name; produced by BASF), Polyquid PA30 (trade name; produced by San 20 yo Chemical) etc.), carboxymethylethyl cellulose, shellac and the like; sustained-release substrates such as methacrylic acid copolymers (e.g., Eudragit NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name), etc.) and the like; water-soluble polymers; plasticizers such as triethyl 25 citrate, polyethylene glycol, acetylated monoglycerides, triacetin, castor oil and the like; and the like, and the like. The above-mentioned "additive" includes, for example, water-soluble sugar alcohols (e.g., sorbitol, mannitol, 30 maltitol, reduced starch saccharides, xylitol, reduced palatinose, erythritol, etc.), crystalline cellulose (e.g., Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, Avicel RC-591 (crystalline cellulose carmellose sodium) etc.), low-substituted hydroxypropyl cellulose (e.g., 35 LH-22, LH-32, LH-23, LH-33 (Shin-Etsu Chemical), mixtures 51 thereof etc.) and the like. Furthermore, binders, souring agents, bubbling agents, sweetening agents, flavorings, lubricants, coloring agents, stabilizers, excipients, disintegrants etc. are also used. 5 The compound of the present invention may be used in combination with 1 to 3 other active ingredients. Such "other active ingredients" include, for example, anti-Helicobacter pylori active substances, imidazole compounds, bismuth salts, quinolone compounds, and so forth. 10 Such "anti-Helicobacter pylori active substances" include, for example, antibiotic penicillins (e.g., amoxicillin, benzylpenicillin, piperacillin, mecillinam, ampicillin, temocillin, bacampicillin, aspoxicillin, sultamicillin, lenampicillin, etc.), antibiotic cefems (e.g., 15 cefixime, cefaclor, etc.), antibiotic macrolides (e.g., erythromycin, clarithromycin, roxithromycin, rokitamycin, flurithromycin, telithromycin, etc.), antibiotic tetracyclines (e.g., tetracycline, minocycline, streptomycin, etc.), antibiotic aminoglycosides (e.g., gentamicin, amikacin, etc.), 20 imipenem and so forth. Of these substances, preferred are antibiotic penicillins, antibiotic macrolides and the like. Such "imidazole compounds" include, for example, metronidazole, miconazole and the like. Such "bismuth salts" include, for example, bismuth 25 acetate, bismuth citrate, bismuth subsalicylate and the like. Such "quinolone compounds" include, for example, ofloxacin, ciploxacin and the like. For eradication of Helicobacter pylori, a compound (I) or a salt thereof of the present invention with antibiotic 3o penicillin (e.g., amoxicillin and the like) and antibiotic erythromycin (e.g., clarithromycin and the like) is preferably used. For the purpose of eradication of Helicobacter pylori, while the compound of the present invention has an anti-H. 35 pylori action (bacteriostatic action or eradication action) by 52 itself, it can enhance the antibacterial action of other antibiotics based on the pH controlling action in the stomach and the like, and also provides an assistant effect such as an eradication effect based on the action of the antibiotics to 5 be used in combination. Such "other active ingredients" and the compound (I) or a salt thereof of the present invention may be mixed, prepared as a single pharmaceutical composition [e.g., tablets, powders, granules, capsules (including soft capsules), lo liquids, injectable preparations, suppositories, sustained release preparations, etc.], in accordance with a commonly known method, and used in combination, and may also be prepared as separate preparations and administered to the same subject simultaneously or at a time interval. 15 In addition, the compound of the present invention may be used in combination with a gastric motility enhancer, a drug acting on lower esophageal sphincter (e.g., temporary lower esophageal sphincter relaxation suppressant etc.), ClC-2 channel opener (intestinal juice secretion enhancer), a 20 histamine H2 receptor antagonist, an antacid, a sedative, a stomachic digestant or a non-steroidal anti-inflammatory drug (NSAID). As the "gastric motility enhancer", for example, domperidone, metoclopramide, mosapride, itopride, tegaserod 25 and the like can be mentioned. As the "a drug acting on lower esophageal sphincter", for example, GABA-B receptor agonists such as baclofen, an optically active form thereof and the like, and the like can be mentioned. 30 As the "ClC-2 channel opener (intestinal juice secretion enhancer)", lubiprostone and the like can be mentioned. As the "histamine H2 receptor antagonist", cimetidine, ranitidine, famotidine, roxatidine, nizatidine, lafutidine and the like can be mentioned. 35 As the "antacid", sodium hydrogencarbonate, aluminum 53 hydroxide and the like can be mentioned. As the "sedatives", diazepam, chlordiazepoxide and the like can be mentioned. As the "stomachic digestant", gentiana, swertia japonica, 5 diastase and the like can be mentioned. As the "non-steroidal anti-inflammatory drug", for example, aspirin, indomethacin, ibuprofen, mefenamic acid, diclofenac, etodorac, piroxicam, celecoxib and the like can be mentioned. 10 A gastric motility enhancer, a drug acting on lower esophageal sphincter, a ClC-2 channel opener (intestinal juice secretion enhancer), a histamine H2 receptor antagonist, an antacid, a sedative, a stomachic digestant or a non-steroidal anti-inflammatory drug and compound (I) or a salt thereof of the 15 present invention may be mixed, prepared as a single pharmaceutical composition [e.g., tablets, powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc.] according to a method known per se for combined use, or may also be 20 prepared as separate preparations and administered to the same subject simultaneously or in a staggered manner. The compound of the present invention may be used in combination with the following drugs. (i) proton pump inhibitors, e.g., omeprazole, 25 esomeprazole, pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lansoprazole; (ii) oral antacid mixtures, e..g., Maalox@, Aludrox@ and Gaviscon®; (iii) mucosal protective agents, e.g., polaprezinc, 3o ecabet sodium, rebamipide, teprenone, cetraxate, sucralfate, chloropylline-copper and plaunotol; (iv) anti-gastric agents, e.g., Anti-gastrin vaccine, itriglumide and Z-360; (v) 5-HT 3 antagonists, e.g., dolasetron, palonosetron, 35 alosetron, azasetron, ramosetron, mitrazapine, granisetron, 54 tropisetron, E-3620, ondansetron and indisetron; (vi) 5-HT 4 agonists, e.g., tegaserod, mosapride, cinitapride and oxtriptane; (vii) laxatives, e.g., Trifyba@, Fybogel@, Konsyl@, 5 Isogel@, Regulan@, Celevac@ and Normacol@; (viii) GAB2k agonists, e.g., baclofen and AZD-3355; (ix) GABA antagonists, e.g., GAS-360 and SGS-742; (x) calcium channel blockers, e.g., aranidipine, lacidipine, falodipine, azelnidipine, clinidipine, lomerizine, lo diltiazem, gallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine, bevantolol, nicardipine, isradipine, benidipine, verapamil, nitrendipine, barnidipine, propafenone, manidipine, bepridil, nifedipine, nilvadipine, nimodipine and fasudil; 15 (xi) dopamine antagonists, e.g., metoclopramide, domperidone and levosulpiride; (xii) Tachykinin (NK) antagonists, particularly NK-3, NK 2 and NK-1 antagonists, e.g., nepadutant, saredutant, talnetant, (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl] 20 8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H [1,4]diazocino[2,1-gl[1,7]naphthridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy 3-(4-fluorophenyl)-4-morpholinyllmethyl]-1,2-dihydro-3H-1,2,4 triazol-3-one (MK-869), lanepitant, dapitant and 3-[[2 25 methoxy-5-(trifluoromethoxy)phenyl methylamino]-2-phenyl piperidine (2S, 3S); (xiii) nitric oxide synthase inhibitors, e.g., GW-274150, tilarginine, P54, guanidioethyldisulfide and nitroflurbiprofen; 30 (xiv) vanilloid receptor 1 antagonists, e.g., AMG-517 and GW-705498; (xv) ghrelin agonists, e.g., capromorelin and TZP-101; (xvi) AchE release stimulants, e.g., Z-338 and KW-5092. The above-mentioned drugs (i)-(xvi) and compound (I) or a 35 salt thereof of the present invention may be mixed, prepared 55 as a single pharmaceutical composition [e.g., tablets, powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc.] according to a method known per se for 5 combined use, or may also be prepared as separate preparations and administered to the same subject simultaneously or in a staggered manner. Examples The present invention is explained in detail in the 10 following by referring to Reference Examples, Examples and Experimental Examples, which are not to be construed as limitative. In the following Reference Examples and Examples, the "room temperature" generally means about 100C to about 350C, 15 but it is not particularly strictly limited. The mixing ratio of liquids shows a volume ratio. Unless otherwise specified, "%" means weight %. The yield is in mol/mol%. Silica gel column chromatography was performed using silica gel 60 (0.063-0.200 mm) manufactured by MERCK or Fuji Silysia 20 Chemical Ltd. Chromatorex (product name) NH (described as basic silica gel column chromatography). The melting point was measured using Yanagimoto trace melting point measurement apparatus or Buechi trace melting point measurement apparatus (B-545), and shown without amendment. For 1 H-NMR spectrum, 25 tetramethylsilane was used as the internal standard, and Varian Gemini-200 (200 MHz), Mercury-300 (300 MHz) spectrometer, Bruker AVANCE AV300 (300 MHz) and JNM-AL400 (400 MHz) nuclear magnetic resonance apparatuses JEOL DATUM (JEOL DATUM LTD.) were used for the measurement. The following 30 abbreviations are used for showing the measurement results. s: singlet, d: doublet, dd: double doublet, dt: double triplet, t: triplet, q: quartet, m: multiplet, br: broad, brs: broad singlet, J: coupling constant, Hz: Hertsz. Reference Example 1 35 2-bromo-l-(2-fluorophenyl)propan-l-one 56 To a solution of 2'-fluoropropiophenone (25.0 g) in acetic acid (250 mL) was slowly added bromine (8.4 mL). The mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. Water (200 mL) was added 5 to the residue, and the mixture was extracted with diisopropyl ether. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow 10 oil (yield 36.8 g, 97%). H-NMR (CDCl 3 )6: 1.89-1.91 (3H, m), 5.27-5.34 (1H, m), 7.12 7.19 (1H, m), 7.24-7.30 (1H, m), 7.52-7.59 (1H, m), 7.88-7.93 (1H, m). Reference Example 2 25 ethyl 2-cyano-4-oxo-4-phenylbutanoate Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (37 mL), and the mixture was stirred at 40-450C for 45 min. A solution (100 mL) of phenacyl bromide (10.0 g) in acetone was added dropwise over 30 min. After completion of 20 the dropwise addition, the mixture was stirred at room temperature for 18 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, 25 dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1-91:1) to give the title 30 compound as a pale-yellow oil (yield 10.41 g, 90%). 'H-NMR (CDCl 3 )6: 1.35 (3H, t, J=7.2 Hz), 3.55 (1H, dd, J=16.0, 5.6 Hz), 3.80 (1H, dd, J=16.0, 7.0 Hz), 4.16 (1H, dd, J=7.0, 5.-6 Hz), 4.31 (2H, q, J=7.2 Hz), 7.40-7.70 (3H, m), 7.90-8.00 (2H, m). 35 Reference Example 3 57 methyl 2-cyano-4-(2-fluorophenyl)-3-methyl-4-oxobutanoate To a solution of methyl cyanoacetate (15.5 mL) and diisopropylethylamine (64 mL) in tetrahydrofuran (110 mL) was added a solution of 2-bromo-1-(2-fluorophenyl)propan-1-one 5 (36.8 g) in tetrahydrofuran (160 mL), and the mixture was stirred at 700C for 20 hr. The reaction mixture was allowed to cool to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography 10 (eluent: hexane-ethyl acetate=5:1) to give the title compound as a brown oil (yield 31.9 g, 80%). 'H-NMR (CDCl 3 )6: 1.42-1.46 (3H, m), 3.82-3.85 (4H, m), 3.99 4.17 (1H, m), 7.14-7.22 (1H, m), 7.25-7.31 (1H, m), 7.55-7.63 (1H, m), 7.85-7.91 (1H, m). 15 Reference Example 4 ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate To a solution of 2'-fluoroacetophenone (28.6 g) in ethyl acetate (400 mL) was added copper (II) bromide (92.6 g), and the mixture was heated under reflux for 4 hr. The reaction 20 mixture was allowed to cool to room temperature and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give crude 2-bromo-1 (2-fluorophenyl)ethanone (yield 90.5 g) as an oil. Potassium carbonate (88 g) was added to ethyl cyanoacetate (168 g), and 25 the mixture was stirred at 450C for 1 hr. A solution (360 mL) of crude 2-bromo-1-(2-fluorophenyl)ethanone (90.5 g) in acetone was added dropwise over 20 min. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr. Water (300 mL) and ethyl acetate (300 3o mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous sodium dihydrogen phosphate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in 35 the obtained oil was evaporated under reduced pressure and the 58 residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=20:1--4:1) to give the title compound as an oil (yield 64.0 g, about 100%). 1 H-NMR (CDCl 3 )S: 1.35 (3H, t, J=7.2 Hz), 3.55-3.80 (2H, m), 5 4.11 (1H, t, J=6.0 Hz), 4.24-4.34 (2H, m), 7.15-7.29 (2H, m), 7.55-7.62 (1H, m), 7.94 (1H, dt, J=7.5, 1.8 Hz). Reference Example 5 ethyl 2-cyano-4-oxo-4-{(2-trifluoromethyl)phenyllbutanoate 2'-(Trifluoromethyl)acetophenone (10.0 g) was dissolved 10 in chloroform (30 mL) and diethyl ether (30 mL), a solution of bromine (8.50 g) in chloroform (20 mL) was added dropwise while maintaining the reaction temperature at not higher than 250C. After the dropwise Addition, the mixture was stirred at room temperature for 1 hr, water was added to the reaction 15 mixture and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentration under reduced pressure to give crude 2-bromo-l-(2-trifluoromethylphenyl)ethanone. Potassium carbonate (13.82 g) was added to ethyl cyanoacetate 20 (44.44 g), and the mixture was stirred at 450C for 1 hr. A solution of crude 2-bromo-1-(2-trifluoromethylphenyl)ethanone in acetone (100 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr, and stirred overnight at room 25 temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under 30 reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography fluentt: hexane-ethyl acetate=9:1-*7:1) to give the title compound as an oil (yield 10.43 g, from 2' 35 (trifluoromethyl)acetophenone, yield 66%). 59 1 H-NMR (CDCl 3 )S: 1.36 (3H, t, J=7.2 Hz), 3.34-3.46 (1H, m), 3.59-3.70 (1H, m), 4.08-4.22 (1H, m), 4.32 (2H, q, J=7.2 Hz), 7.57-7.80 (4H, m). Reference Example 6 5 ethyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate To a solution (60 mL) of ethyl 2-cyano-4-oxo-4 phenylbutanoate (5.0 g) in tetrahydrofuran was blown in hydrogen chloride (28 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Then, nitrogen was 10 blown in to remove excess hydrogen chloride. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1) to give the title compound as a pale-yellow solid (yield 4.24 g, 79%). 15 1 H-NMR (CDCl 3 )S: 1.37 (3H, t, J=6.8 Hz), 4.33 (2H, q, J=6.8 Hz), 6.87 (1H, d, J=3.2 Hz), 7.20-7.60 (5H, m), 8.79 (1H, br). Reference Example 7 ethyl 2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate A mixture of ethyl 2-cyano-4-(2-fluorophenyl)-4 20 oxobutanoate (19.3 g) and 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1-+3:1) to give 25 the title compound as a brown solid (yield 8.76 g, 53%). 'H-NMR (CDCl 3 )5: 1.36-1.41 (3H, m), 4.33 (2H, q, J=7.2 Hz), 6.99-7.00 (1H, m), 7.09-7.26 (3H, m), 7.55-7.61 (1H, m), 9.08 (1H, brs). Reference Example 8 3o methyl 2-chloro-5-(2-fluorophenyl)-4-methyl-lH-pyrrole-3 carboxylate To a solution of methyl 2-cyano-4-(2-fluorophenyl)-3 methyl-4-oxobutanoate (31.0 g) in ethyl acetate (30 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (150 35 mL), and the mixture was stirred at room temperature for 2 60 days. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed twice with water, and then washed with saturated aqueous sodium hydrogencarbonate solution, dried over 5 anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title.compound as white crystals (yield 19.3 g, 58%). 1 H-NMR (CDCl 3 )S: 2.33 (3H, s), 3.86 (3H, s), 7.12-7.42 (4H, m), 10 8.53 (1H, brs). Reference Example 9 ethyl 5-phenyl-1H-pyrrole-3-carboxylate To a solution (50 mL) of ethyl 2-chloro-5-phenyl-1H pyrrole-3-carboxylate (8.5 g) in ethanol was added 10% 15 palladium carbon (50% containing water, 0.5 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography 20 (eluent: hexane-ethyl acetate=9:1-+1:1) to give the title compound as a colorless solid (yield 4.50 g, 62%). 'H-NMR (CDCl 3 )S: 1.36 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 6.91 (1H, m), 7.20-7.70 (6H, m), 8.77 (1H, br). Reference Example 10 25 ethyl 5-(2-fluorophenyl)-lH-pyrrole-3-carboxylate To a solution (80 mL) of ethyl 2-chloro-5-(2 fluorophenyl)-1H-pyrrole-3-carboxylate (8.6 g) in ethanol was added 10% palladium carbon (50% containing water, 0.86 g), and the mixture was stirred under a hydrogen atmosphere at room 30 temperature for 36 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (70 mL), 10% palladium carbon (50% containing water, 0.90 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 60 35 hr. The reaction mixture was filtered, and the filtrate was 61 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1- 5:1) to give the title compound as a brown solid (yield 1.37 g, 18%). 5 1H-NMR (CDCl 3 )S: 1.67 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 7.03-7.05 (1H, m), 7.08-7.25 (3H, m), 7.49-7.50 (1H, m), 7.58-7.66 (1H, m), 9.22 (1H, brs). Reference Example 11 methyl 5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carboxylate 10 To a solution of methyl 2-chloro-5-(2-fluorophenyl)-4 methyl-lH-pyrrole-3-carboxylate (10.2 g) in methanol (200 mI) was added 10% palladium carbon (50% containing water, 1.28 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 20 hr. The reaction mixture was filtered, 15 and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution (100 mL) was added to the residue, and the mixture was extracted with ethyl.acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, 20 dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound as white crystals (yield 6.70 g, 76%). 'H-NMR (CDCl 3 )S: 2.40 (3H, s), 3.82 (3H, s), 7.12-7.33 (3H, m), 25 7.42-7.49 (2H, m), 8.67 (1H, brs). Reference Example 12 ethyl 5-[(2-trifluoromethyl)phenyl]-lH-pyrrole-3-carboxylate By a similar operation as in Reference Examples 7 and 9 and using ethyl 2-cyano-4-oxo-4-[(2 30 trifluoromethyl)phenyl]butanoate, the title compound was obtained as colorless crystals. More specifically, a mixture of ethyl 2-cyano-4-[(2-trifluoromethyl)phenyll-4-oxobutanoate (10.2 g) and 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) was stirred at room temperature for 18 hr. The 35 reaction mixture was concentrated under reduced pressure, and 62 the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1-+3:1) to give ethyl 2 chloro-5-[(2-trifluoromethyl)phenyll-lH-pyrrole-3-carboxylate as a brown solid (yield 6.37 g, 59%) . This was dissolved in 5 ethanol (120 mL), 10% palladium carbon (50% containing water, 0.5 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column 10 chromatography (eluent: hexane-ethyl acetate=9:1-+1:1) to give the title compound as a colorless solid (yield 2.89 g, 51%). 1 H-NMR (CDCl 3 )5: 1.36 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 6.81 (1H, s), 7.42-7.61 (5H, m), 8.69 (1H, br). Reference Example 13 15 (5-phenyl-1H-pyrrol-3-yl)methanol A solution (100 mL) of ethyl 5-phenyl-1H-pyrrole-3 carboxylate (2.16 g) in tetrahydrofuran was cooled to -780C, and a 1.5 mol/L solution (24 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min. The mixture was 20 further stirred at -780C for.1 hr, water (2 mL) was added dropwise over 2 min, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was filtered using celite and anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a pale 25 red powder (yield 1.51 g, 87%). 1 H-NMR (DMSO-d 6 )5: 4.34 (2H, d, J=5.4 Hz), 4.60 (1H, t, J=5.4 Hz), 6.45-6.46 (1H, m), 6.74 (1H, br), 7.11-7.15 (1H, m), 7.31-7.35 (2H, m), 7.57-7.59 (2H, m), 11.05 (1H, s). Reference Example 14 30 [5-(2-fluorophenyl)-4-methyl-lH-pyrrol-3-yl]methanol By a similar operation as in Reference Example 13 and using methyl 5-(2-fluorophenyl)-4-methyl-lH-pyrrole-3 carboxylate (1.63 g) and a solution (15 mL) of 1.5 mol/L diisobutylaluminum hydride in toluene, the title compound was 35 obtained as white crystals (yield 1.18 g, 82%). 63 1 H-NMR (CDC1 3 )6: 1.30 (1H, t, J=4.8 Hz), 2.25 (3H, s), 4.61 (2H, d, J=4.8 Hz), 6.87 (1H, d, J=3.3 Hz), 7.10-7.28 (3H, m), 7.44-7.50 (1H, m), 8.40 (1H, brs). Reference Example 15 5 5-phenyl-1H-pyrrole-3-carbaldehyde To a solution (45 mL) of (5-phenyl-1H-pyrrol-3 yl)methanol (1.51 g) in acetonitrile were added tetra-n propylammonium perruthenate (0.46 g), N-methylmorpholine N oxide (2.36 g) and molecular sieves 4A powder (4.5 g), and the 10 mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane ethyl acetate=4:1-+1:1) to give the title compound as a pale 15 yellow powder (yield 0.92 g, 62%). 1 H-NMR (CDCl 3 )S: 6.95 (1H, m), 7.29-7.32 (1H, m), 7.40-7.44 (2H, m), 7.50-7.52 (3H, m), 9.02 (1H, br), 9.84 (1H, s). Reference Example 16 5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carbaldehyde 20 By a similar operation as in Reference Example 15 and using [5-(2-fluorophenyl)-4-methyl-1H-pyrrol-3-yl]methanol (1.17 g), tetra-n-propylammonium perruthenate (101 mg), N methylmorpholine N-oxide (1.01 g) and molecular sieves 4A powder (572 mg), the title compound was obtained as pale-pink 25 crystals (yield 0.67 g, 58%). 'H-NMR (CDC1 3 )S: 2.45 (3H, s), 7.14-7.36 (3H, m), 7.44-7.50 (2H, m), 8.82 (1H, brs), 9.92 (1H, s). Reference Example 17 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde 30 A solution (220 mL) of ethyl 5-(2-fluorophenyl)-1H pyrrole-3-carboxylate (11.6 g) in tetrahydrofuran was cooled to -780C, and a 1.5 mol/L solution (100 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min. The mixture was stirred at -780C for 1 hr and water (10 35 mL) was added dropwise over 2 min. The mixture was allowed to 64 warm to room temperature and the mixture was stirred for 2 hr. The reaction mixture was filtered by adding celite and anhydrous magnesium sulfate and concentrated under reduced pressure to give a pale-yellow oil (yield 8.3 g) . To a 5 solution (220 mL) of the obtained pale-yellow oil (8.30 g) in acetonitrile were added tetra-n-propylammonium perruthenate (1.75 g), N-methylmorpholine N-oxide (13.5 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered 10 through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3-1:1) to give the title compound as yellow crystals (yield 5.6 g, 60%). 15 'H-NMR (CDCl 3 )6: 7.07-7.28 (4H, m), 7.52-7.54 (1H, m), 7.61 7.67 (1H, m), 9.49 (1H, brs), 9.86 (1H, s). Reference Example 18 5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde A solution (28 mL) of ethyl 5-[2 20 (trifluoromethyl)phenyll-1H-pyrrole-3-carboxylate (1.38 g) in tetrahydrofuran was cooled to -780C, and a 1.5 mol/L solution (13 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min. The mixture was further stirred at -78oC for 1 hr, and water (3 mL) was added dropwise over 2 min. The 25 mixture was allowed to warm to room temperature and the mixture was further stirred for 1 hr. The reaction mixture was filtered by adding celite and anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to give a pale-yellow oil (yield 1.14 g) . The obtained oil (1.14 g) was 30 dissolved in acetonitrile (50 mL), and tetra-n-propylammonium perruthenate (0.26 g), N-methylmorpholine N-oxide (1.32 g) and molecular sieves 4A powder (5 g) were added to this solution. The mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate 35 was concentrated under reduced pressure. The residue was 65 purified by silica gel column chromatography (eluent: hexane ethyl acetate=4:1-+l:1) to give the title compound as colorless crystals (yield 0.71 g, 61%). 'H-NMR (CDCl 3 )5: 6.79-6.81 (1H, m), 7.46-7.78 (5H, m), 9.13 5 (1H, br), 9.82 (1H, s). Reference Example 19 . methyl 1H-pyrrole-3-carboxylate To a suspension of potassium tert-butoxide (17.9 g) in tetrahydrofuran (200 mL) was added dropwise a solution of p 10 toluenesulfonylmethyl isocyanide (25.2 g) and methyl acrylate (11.8 mL) in tetrahydrofuran (200 mL) over 30 min. The reaction mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium 15 hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a white solid (yield 6.56 g, 41%). 20 1 H-NMR (CDCl 3 )S: 3.82 (3H, s), 6.15 (1H, m), 6.75 (1H, m), 7.43 (1H, m), 8.50 (1H, brs). Reference Example 20 methyl 4-methyl-1H-pyrrole-3-carboxylate By a similar operation as in Reference Example 19 and 25 using p-toluenesulfonylmethyl isocyanide (94.6 g), methyl crotonate (48.5 g) and potassium tert-butoxide (76.7 g), the title compound was obtained as a pale-yellow solid (yield 16.8 g, 25%). H-NMR (CDCl 3 )S: 2.29 (3H, s), 3.80 (3H, s), 6.53-6.54 (iH, m), 3o 7.36-7.38 (1H, m), 8.25 (1H, brs). Reference Example 21 ethyl 2-methyl-lH-pyrrole-3-carboxylate Vinyl acetate (13.4 g) was added dropwise over 2 hr to bromine (25 g) under ice-cooling with stirring. The reaction 35 mixture was further stirred at the same temperature for 1 hr. 66 Ethyl 3-oxobutanoate (18.5 g) was added, and 25% aqueous ammonia solution (44 mL) was added dropwise over 1 hr. The reaction mixture was further stirred at room temperature for 30 min, water was added and the mixture was extracted with 5 ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-+3:1) and recrystallized from hexane to give the title compound as a lo colorless solid (yield 7.56 g, 35%). 1 H-NMR (CDCl 3 )6: 1.32-1.37 (3H, m), 2.53 (3H, s), 4.24-4.31 (2H, m), 6.55-6.58 (2H, m), 8.13 (1H, br). Reference Example 22 methyl 5-bromo-lH-pyrrole-3-carboxylate 15 A solution (30 mL) of methyl 1H-pyrrole-3-carboxylate (3.06 g) in tetrahydrofuran was cooled to -780C, N bromosuccinimide (4.38 g) and then pyridine (3 drops) were added, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction mixture, and the mixture 20 was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl 25 acetate=5:1) to give the title compound as a pale-yellow solid (yield 3.08 g, 62%). H-NMR (CDCl 3 )S: 3.81 (3H, s), 6.58 (1H, m), 7.36 (1H, m), 8.60 (1H, brs). Reference Example 23 30 methyl 5-bromo-4-methyl-lH-pyrrole-3-carboxylate By a similar operation as in Reference Example 22 and using methyl 4-methyl-1H-pyrrole-3-carboxylate (1.0 g) and N bromosuccinimide (1.28 g), the title compound was obtained as a pale-yellow solid (yield 489 mg, 31%). 35 1 H-NMR (CDCl 3 )S: 2.23 (3H, s), 3.80 (3H, s), 7.37 (1H, d, J=3.0 67 Hz), 8.40 (1H, brs). Reference Example 24 ethyl 5-bromo-2-methyl-1H-pyrrole-3-carboxylate To a solution of ethyl 2-methyl-lH-pyrrole-3-carboxylate 5 (1.53 g) in tetrahydrofuran (20 mL) was added N bromosuccinimide (1.78 g) at -780C, and the mixture was stirred at the same temperature for 30 min. Water and diethyl ether were added to extract the reaction mixture. The extract was washed with saturated brine, dried over anhydrous magnesium 10 sulfate, and concentrated under reduced pressure at 5oC or below. The residue was washed with hexane to give the title compound as a colorless solid (yield 2.26 g, 97%). 1 H-NMR (CDCl 3 )5: 1.30-1.35 (3H, m), 2.51 (3H, s), 4.22-4.29 (2H, m), 6.50 (1H, s), 8.01 (1H, br). 15 Reference Example 25 2-hydroxy-5-pyrimidinesulfonic acid Fuming sulfuric acid (containing 25% sulfur dioxide, 100 mL) was cooled to OC, and 2-aminopyrimidine (25 g) was gradually added over 1 hr. The mixture was heated to 1800C and 20 stirred for 40 hr. After cooling to room temperature, the mixture was poured into ice (1 kg). The precipitate was collected by filtration and recrystallized from water to give the title compound (yield 25.6 g, 55%). 1 H-NMR (DMSO-d 6 )6: 6.20-7.20 (2H, m), 8.71 (2H, s). 25 Reference Example 26 2-chloro-5-pyrimidinesulfonyl chloride A mixture of 2-hydroxy-5-pyrimidinesulfonic acid (12.8 g) and phosphorus pentachloride (37.8 g) was stirred at 1800C for 4 hr. After cooling to room temperature, toluene (200 mL) was 3o added, and the insoluble material was filtered off. The filtrate was washed with ice water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was stood in a freezer for one day to give the title compound as a pale-yellow solid (yield 35 14.8 g, 96%). 68 H-NMR (CDCl 3 )5: 9.19 (2H, s). Reference Example 27 6-chloropyridazine-3-thiol To a suspension (88 mL) of sodium hydrogensulfide (3.78 5 g) in ethanol was added 3,6-dichloropyridazine (5.0 g), and the mixture was refluxed for 1 hr. The solvent was evaporated under reduced pressure, and water (12.5 mL) was added. The mixture was adjusted to about pH 9 with 2 mol/L sodium hydroxide solution, and the precipitate was filtered off. The 10 filtrate was adjusted to about pH 2 with 6 mol/L hydrochloric acid and the precipitate was collected by filtration to give the title compound as a yellow solid (yield 4.74 g, 96%). 'H-NMR (CDCl 3 )S: 6.99 (1H, d, J=9.6 Hz), 7.60 (1H, d, J=9.6 Hz). 15 Reference Example 28 6-chloropyridazine-3-sulfonyl fluoride To a mixture cooled to -200C of methanol (10 mL) and water (10 mL) were added potassium hydrogenfluoride (16 g) and 6-chloropyridazine-3-thiol (2.37 g) . After stirring at the 20 same temperature for 20 min, chlorine was blown in for 30 min. Ice water (20 mL) was added and the precipitate was collected by filtration. The precipitate was extracted with ethyl acetate and water. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent 25 was evaporated under reduced pressure to allow crystallization, and the crystals were washed with hexane to give the title compound as a gray solid (yield 1.68 g, 53%). 'H-NMR (CDCl 3 )S: 7.86-7.89 (1H, m), 8.17-8.19 (1H, m). Reference Example 29 3o pyridin-3-ylsulfonyl chloride hydrochloride A mixture of 3-pyridinesulfonic acid (50.0 g), phosphorus pentachloride (80.0 g) and phosphorus oxychloride (100 mL) was stirred at 1200C for 8 hr. Under a nitrogen atmosphere, the mixture was cooled to room temperature, and chloroform 35 (dehydrated, 330 mL) was added. Hydrogen chloride was blown 69 in, and the precipitated crystals were collected by filtration and washed with chloroform (dehydrated) to give the title compound as a white solid (yield 54.7 g, 81%). 1 H-NMR (DMSO-d 6 )S: 8.03-8.07 (1H, m), 8.68 (1H, d, J=8.1 Hz), 5 8.87 (1H, d, J=5.7 Hz), 9.01 (1H, s). Reference Example 30 6-methoxypyridin-3-ylsulfonyl chloride 5-Amino-2-methoxypyridine (1.24 g) was dissolved in acetic acid (8.3 mL), and the mixture was stirred under ice 10 cooling. Concentrated hydrochloric acid (8.3 mL) was added, and an aqueous solution (5 mL) of sodium nitrite (689 mg) was added dropwise over 15 min while keeping the inside temperature at not higher than 100C. The reaction mixture was stirred for 10 min, and gradually added at 50C to a mixture of 15 cuprous chloride (280 mg) and acetic acid (17 mL) saturated in advance with sulfur dioxide gas. The mixture was allowed to gradually warm to room temperature until the generation of gas stopped. The reaction mixture was concentrated to about 5 mL under reduced pressure, and the precipitate was collected by 20 filtration to give the title compound (yield 1.0 g, 51%) as crude crystals. This compound was used for the next reaction without purification. Reference Example 31 6-chloropyridin-3-ylsulfonyl chloride 25 Under ice-cooling, thionyl chloride (12 mL) was added dropwise over 1 hr to water (70 mL) and the mixture was stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Separately, under ice-cooling, 5 amino-2-chloropyridine (5.0 g) was added to concentrated 3o hydrochloric acid (40 mL) and the mixture was stirred. An aqueous solution (12.5 mL) of sodium nitrite (2.88 g) was added dropwise while keeping the inside temperature at not higher than 5 0 C, and the mixture was further stirred for 15 min. The reaction mixture was gradually added at 5 0 C to the 35 above-mentioned sulfur dioxide-containing solution added with 70 cuprous chloride (70 mg). Under ice-cooling, the mixture was further stirred for 30 min. The precipitate was collected by filtration, and washed with water and ethanol to give the title compound (yield 4.79 g, 58%). 5 1H-NMR (CDCl 3 )8: 7.60-7.63 (1H, m), 8.24-8.27 (1H, m), 9.03 9.04 (1H, m). Reference Example 32 2-chloro-3-pyridinesulfonyl chloride Under ice-cooling, thionyl chloride (24 mL) was added 10 dropwise over 1 hr to water (140 mL) and the mixture was stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Separately, under ice-cooling, 3 aino-2-chloropyridine (10 g) was added to concentrated hydrochloric acid (80 mL) and the mixture was stirred. An 15 aqueous solution (25 mL) of sodium nitrite (5.75 g) was added dropwise while keeping the inside temperature at not higher than 50C, and the mixture was further stirred for 15 min. The reaction mixture was gradually added at 50C to the above mentioned sulfur dioxide-containing solution added with 20 cuprous chloride (140 mg). Under ice-cooling, the mixture was further stirred for 30 min, and the precipitate was collected by filtration and washed with water and ethanol to give the title compound (yield 6.99 g, 42%). 'H-NMR (CDCl 3 )S: 7.54-7.56 (1H, m), 8.46-8.48 (1H, m), 8.71 25 8.73 (1H, m). Reference Example 33 6-chloro-5-methylpyridine-3-amine Reduced iron (793 mg) was added to an aqueous solution (25 mL) of ammonium chloride (1.27 g), and the mixture was 30 stirred at room temperature for 5 min. A solution (10 mL) of 2-chloro-3-methyl-5-nitropyridine (816 mg) in methanol was added dropwise over 10 min. The reaction mixture was stirred at 400C for 20 min and at 500C for 1.5 hr and further refluxed for 1 hr. The reaction mixture was filtered through celite, 35 and celite was washed with methanol. Methanol was mostly 71 removed by concentration under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium 5 sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-*7:3) to give the title compound as a solid (yield 280 mg, 42%). 'H-NMR (CDCl 3 )5: 3.62 (2H, br), 6.88-6.89 (1H, m), 7.70-7.71 10 (lH, m). Reference Example 34 6-chloro-5-methylpyridine-3-sulfonyl chloride Under ice-cooling, thionyl chloride (0.6 mL) was added dropwise over 30 min to water (3.4 mL) . The mixture was 15 stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Separately, under ice-cooling, 6 chloro-5-methylpyridine-3-amine (278 mg) was added to concentrated hydrochloric acid (6 mL) and the mixture was stirred. An aqueous solution (2 mL) of sodium nitrite (148 mg) 20 was added dropwise while keeping the inside temperature at not higher than 50C, and the mixture was further stirred for 15 min. The reaction mixture was gradually added at 5 0 C to the above-mentioned sulfur dioxide-containing solution added with cuprous chloride (5 mg). Under ice-cooling, the mixture was 25 further stirred for 30 min, and the precipitate was collected by filtration and washed with water to give the title compound as a pale-yellow solid (yield 271 mg, 62%). 1 H-NMR (CDCl 3 )S: 2.54 (3H, s), 8.15 (1H, s), 8.86 (1H, s). Reference Example 35 3o 2-pyridinesulfonyl chloride Under ice-cooling, 2-mercaptopyridine (2.0 g) was added to sulfuric acid (50 mL) and the mixture was stirred. Sodium hypochlorite solution (chlorine content 5%, 126 mL) was added dropwise over 1.5 hr, and the mixture was further stirred at 35 the same temperature for 30 min. The reaction mixture was 72 diluted with water (100 mL), and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a colorless oil 5 (yield 2.45 g, 77%). H-NMR (CDCls) : 7.69-7.71 (1H, m), 8.06-8.14 (2H, m), 8.83 8.85 (1H, ma). Reference Example 36 ethyl 1-[(2-chloro-5-pyrimidine)sulfonyl]-5-phenyl-iH-pyrrole 10 3-carboxylate Ethyl 5-phenyl-1H-pyrrole-3-carboxylate (1.60 g) was dissolved in tetrahydrofuran (50 mL), sodium hydride (60% in oil, 446 mg) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (2.24 mL) was added and the 15 mixture was further stirred at the same temperature for 15 min. 2-Chloro-5-pyrimidinesulfonyl chloride (2.06 g) was added and the reaction mixture was stirred at room temperature for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated 20 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-7:3) to give the title compound as a yellow oil (yield 2.03 g, 70%). 25 'H-NMR (CDCl 3 )5: 1.35-1.39 (3H, m), 4.30-4.37 (2H, m), 6.64 (1H, s), 7.22-7.26 (2H, m), 7.37-7.51 (3H, m), 8.04 (1H, s), 8.37 (2H, s). Reference Example 37 ethyl 1-[(2-methyl-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole 30 3-carboxylate Under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (87 mg) and 2 mol/L trimethylaluminum-hexane solution (1.5 mL) were added to a solution of ethyl 1-[(2-chloro-5-pyrimidine)sulfonyl]-5 35 phenyl-1H-pyrrole-3-carboxylate (588 mg) in tetrahydrofuran 73 (20 mL) with stirring. The mixture was stirred at room temperature for 15 min and 2 mol/L trimethylaluminum-hexane solution (1 mL) was added. After stirring at the same temperature for 20 min, ice water (100 mL) and ammonium 5 chloride (2.0 g) were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl 10 acetate=19:1->1:1) to give the title compound 'as a pale-yellow oil (yield 350 mg, 63%). 1 H-NMR (CDC1 3 )5: 1.34-1.39 (3H, m), 2.77 (3H, s), 4.29-4.36 (2H, m), 6.61 (1H, s), 7.21-7.26 (2H, m), 7.37-7.49 (3H, m), 8.06 (1H, s), 8.41 (2H, s). 15 Reference Example 38 ethyl 1-[(2-amino-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole 3-carboxylate 7 mol/L ammonia-methanol solution (1.0 mL) was added to a solution of ethyl 1-[(2-chloro-5-pyrimidine)sulfonyll-5 20 phenyl-1H-pyrrole-3-carboxylate (392 mg) in tetrahydrofuran (10 mL) with stirring. The mixture was stirred at room temperature for 20 min, saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with 25 saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a colorless solid (yield 373 mg, about 100%). 1 H-NMR (CDCl 3 )5: 1.34-1.39 (3H, m), 4.28-4.36 (2H, m), 5.60 (2H, br), 6.59 (1H, s), 7.26-7.46 (5H, m), 8.02-8.03 (3H, m). 30 Reference Example 39 ethyl 1-(imidazo[1,2-alpyrimidin-6-ylsulfonyl)-5-phenyl-l1H pyrrole-3-carboxylate A mixture of ethyl 1-[(2-amino-5-pyrimidine)sulfonyl]-5 phenyl-1H-pyrrole-3-carboxylate (373 mg), 2-bromo-1,1 35 diethoxyethane (394 mg) and acetic acid (20 mL) was stirred in 74 a microwave reaction apparatus at 1300C for 30 min. After cooling to room temperature, the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was 5 extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-yethyl acetate) to give the title compound as a 10 brown solid (yield 157 mg, 40%). 1 H-NMR (CDCl 3 )5: 1.35-1.40 (3H, m), 4.30-4.37 (2H, m), 6.61 (1H, s), 7.17-7.49 (2H, m), 7.26-7.49 (4H, m), 7.94 (1H, s), 7.99 (1H, s), 8.11 (1H, s), 8.38 (1H, s). Reference Example 40 15 ethyl 5-phenyl-1-(pyridazin-3-ylsulfonyl)-1H-pyrrole-3 carboxylate Ethyl 5-phenyl-1H-pyrrole-3-carboxylate (1.06 g) was dissolved in tetrahydrofuran (30 mL), sodium hydride (60% in oil, 300 mg) was added and the mixture was stirred at room 20 temperature for 15 min. 15-Crown-5 (1.52 mL) was added and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridazine-3-sulfonyl fluoride (1.28 g) was added and the reaction mixture was stirred at room temperature for 30 min. Hydrazine (1.60 g) was added and the reaction mixture 25 was stirred at room temperature for 15 min. Saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue 30 was dissolved in tetrahydrofuran (30 mL), manganese dioxide (75% chemically treated product, 5.0 g) was added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under 35 reduced pressure, and the residue was purified by silica gel 75 column chromatography (eluent: hexane-ethyl acetate=19:1-1:1) to give the title compound (yield 613 mg, yield 24% (containing impurity)). 'H-NMR (CDCl 3 )S: 1.34-1.39 (3H, m), 4.29-4.36 (2H, m), 6.61 5 (1H, s), 7.11-7.22 (2H, m), 7.24-7.51 (5H, m), 8.20 (1H, s), 9.28-9.30 (1H, s). Reference Example 41 methyl 5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate Sodium hydride (60% in oil, 1.1 g) was washed with 10 hexane, and suspended in N,N-dimethylformamide (50 mL). A solution (10 mL) of methyl 5-bromo-lH-pyrrole-3-carboxylate (5.0 g) in N,N-dimethylformamide was added to the suspension at 00C. After stirring at 00C for 30 min, a solution of benzenesulfonyl chloride (3.3 mL) in N,N-dimethylformamide (5 15 mL) was added, and the reaction mixture was stirred at room temperature for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and 20 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=5:1) to give the title compound as a colorless solid (yield 8.5 g, 99%). 1 H-NMR (CDCl 3 )5: 3.83 (3H, s), 6.68 (1H, d, J=2.1 Hz), 7.55 25 7.60 (2H, m), 7.67-7.72 (1H, m), 7.96-7.99 (2H, m), 8.08 (1H, d, J=2.1 Hz). Reference Example 42 methyl 5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3 carboxylate 30 Sodium hydride (60% in oil, 202 mg) was washed with hexane and suspended in N,N-dimethylformamide (10 mL). A solution (10 mL) of methyl 5-bromo-4-methyl-1H-pyrrole-3 ca'rboxylate (1.0 g) in N,N-dimethylformamide was added dropwise at -780C. After completion of the dropwise addition, 35 the reaction mixture was stirred at room temperature for 30 76 min and added dropwise to an ice-cooled solution (10 mL) of benzenesulfonyl chloride (0.71 mL) in N,N-dimethylformamide. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hr, and 5 concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound as a brown solid (yield 1.13 g, 69%). 1 H-NNR (CDCl 3 )5: 2.11 (3H, s), 3.79 (3H, s), 7.45-7.70 (3H, m), 7.85-7.95 (2H, m), 8.06 (1H, s). 10 Reference Example 43 ethyl 2-methyl-i-(phenylsulfonyl)-1H-pyrrole-3-carboxylate By a similar operation as in Reference Example 41 and using ethyl 2-methyl-1H-pyrrole-3-carboxylate (8.81 g), sodium hydride (60% in oil, 2.58 g) and benzenesulfonyl chloride (7.8 15 mL), the title compound was obtained as white crystals (yield 14.3 g, 85%). 1 H-NMR (CDCl 3 )5: 1.31 (3H, t, J=7.2 Hz), 2.62 (3H, s), 4.24 (2H, q, J=7.2 Hz), 6.63 (1H, d, J=3.3 Hz), 7.30 (1H, d, J=3.3 Hz), 7.51-7.57 (2H, m), 7.62-7.68 (1H, m), 7.81-7.84 (2H, m). 20 Reference Example 44 ethyl 5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carboxylate Ethyl 5-bromo-2-methyl-1H-pyrrole-3-carboxylate (2.26 g) was dissolved in tetrahydrofuran (100 mL), sodium hydride (60% 25 in oil, 1.16 g) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (5.90 mL) was added and the mixture was further stirred at the same temperature for 15 min. 3-Pyridinesulfonyl chloride hydrochloride (3.13 g) was added and the reaction mixture was stirred at room temperature 30 for 1 hr. Saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column 35 chromatography (eluent: hexane-ethyl acetate=19:1-+7:3) to give 77 the title compound as a yellow oil (yield 2.31 g, 64%). 1 H-NMR (CDCl 3 )5: 1.24-1.34 (3H, m), 2.94 (3H, s), 4.23-4.30 (2H, m), 6.69 (1H, s), 7.51-7.55 (1 , m), 8.17-8.21 (1H, m), 8.88-8.91 (1H, m), 9.14 (1H, m). 5 Reference Example 45 ethyl 2-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carboxylate A suspension of ethyl 5-bromo-2-methyl-1-(pyridin-3 ylsulfonyl)-1H-pyrrole-3-carboxylate (2.26 g), phenylboronic io acid (1.54 g), dichlorolbis(triphenylphosphine)lpalladium (211 mg) and sodium carbonate (1.91 g) in 1,2-dimethoxyethane (20 mL)-water (10 mL) was stirred at 800C for 40 min. After cooling, the reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The organic layer was 15 separated from the filtrate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1-+6:4) to give the title compound as a colorless oil 20 (yield 2.39 g, about 100%). 1 H-NMR (CDCl 3 )5: 1.30-1.34 (3H, m), 2.92 (3H, s), 4.23-4.30 (2H, m), 6.59 (1H, s), 7.23-7.39 (4H, m), 7.50-7.68 (2H, m), 8.22-8.25 (1H, m), 8.61-8.62 (1H, m), 8.75-8.77 (1H, m). Reference Example 46 25 [5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl methanol A solution (80 mL) of methyl 5-bromo-1-(phenylsulfonyl) 1H-pyrrole-3-carboxylate (7.1 g) in tetrahydrofuran was cooled to -780C, a 1.5 mol/L solution (42 mL) of diisobutylaluminum hydride in toluene was added dropwise over 30 min and the 30 mixture was further stirred at -780C for 1 hr. 1 mol/L hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous 35 sodium sulfate, and concentrated under reduced pressure to 78 give the title compound as a brown oil (yield 7.1 g, about 100%). 'H-NMR (CDCl 3 )S: 1.62 (1H, brs), 4.51 (2H, s), 6.33-6.34 (1H, m), 7.44-7.45 (1H, m), 7.51-7.57 (2H, m), 7.62-7.68 (1H, m), 5 7.93-7.97 (2H, m). Reference Example 47 [2-methyl-i-(phenylsulfonyl)-lH-pyrrol-3-yl]methanol By a similar operation as in Reference Example 13 and using ethyl 2-methyl-i-(phenylsulfonyl)-lH-pyrrole-3 10 carboxylate (8.05 g) and 1.5 mol/L diisobutylaluminum hydride toluene solution (55 mL), the title compound was obtained as white crystals (yield 6.61 g, 96%). 'H-NMR (CDCl 3 )6: 1.37 (1H, brs), 2.29 (3H, s), 4.42 (2H, brs), 6.29 (1H, d, J=3.6 Hz), 7.30 (1H, d, J=3.6 Hz), 7.49-7.55 (2H, 15 m), 7.58-7.64 (1H, m), 7.78-7.81 (2H, m). Reference Example 48 5-bromo-l-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde To a solution (80 mL) of [5-bromo-l-(phenylsulfonyl)-lH pyrrol-3-yl]methanol (7.1 g) in acetonitrile were added tetra 20 n-propylammonium perruthenate (0.63 g), N-methylmorpholine N oxide hydrate (4.2 g) and molecular sieves 4A powder (3.5 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the 25 residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound 30 as a colorless solid (yield 4.6 g, 71%). 1 H-NMR (CDCl 3 )5: 6.73 (1H, d, J=2.1 Hz), 7.57-7.63 (2H, m), 7.70-7.75 (1H, m), 7.98-8.02 (2H, m), 8.10 (1H, d, J=2.1 Hz), 9.77 (1H, s). Reference Example 49 35 5-bromo-4-methyl-l-(phenylsulfonyl)-lH-pyrrole-3-carbaldehyde 79 By a similar reaction as in Reference Example 17 and using methyl 5-bromo-4-methyl-l-(phenylsulfonyl)-1H-pyrrole-3 carboxylate, the title compound was obtained as a colorless solid (1.78 g, 54%). 5 1H-NMR (CDCl 3 )S: 2.14 (3H, s), 7.50-7.62 (3H, m), 7.91-7.96 (2H, m), 8.04 (1H, s), 9.77 (1H, s). Reference Example 50 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde A suspension of 5-bromo-4-methyl-l-(phenylsulfonyl)-lH 10 pyrrole-3-carbaldehyde (1.78 g), phenylboronic acid (1.37 g), dichloro[bis(triphenylphosphine))palladium (0.19 g) and sodium carbonate (1.72 g) in 1,2-dimethoxyethane (30 mL)-water (10 mL) was stirred at 1000C for 1 hr. 8 mol/L aqueous sodium hydroxide solution (15 mL) was added, and the mixture was 15 stirred at 900C for 3 hr. After cooling, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl 20 acetate=9:1->1:1), and the obtained solid was washed with hexane to give the title compound as a pale-yellow solid (yield 815 mg, 69%). 'H-NMR (CDCl 3 )5: 2.47 (3H, s), 7.34-7.48 (6H, m), 8.58 (1H, br), 9.91 (1H, s). 25 Reference Example 51 2-methyl-l-(phenylsulfonyl)-lH-pyrrole-3-carbaldehyde To a mixture of [2-methyl-l-(phenylsulfonyl)-1H-pyrrol-3 yl]methanol (6.35 g), dimethyl sulfoxide (50 mL) and triethylamine (25 mL) was added sulfur trioxide.pyridine 30 complex (4.57 g), and the mixture was stirred at room temperature for 12 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate 35 solution, water and saturated brine, dried over anhydrous 80 sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give a white title compound (yield 5.27 g, 84%). 5 'H-NMR (CDCl 5 )6: 2.62 (3H, s), 6.65 (1H, d, J=3.6 Hz), 7.35 (1H, d, J=3.6 Hz), 7.55-7.61 (2H, m), 7.66-7.71 (1H, m), 7.85 7.88 (2H, m), 9.89 (1H, s). Reference Example 52 2-methyl-1H-pyrrole-3-carbaldehyde 10 To a solution of 2-methyl-l-(phenylsulfonyl)-1H-pyrrole 3-carbaldehyde (4.59 g) in tetrahydrofuran (20 mL) and methanol (5 mL) was added 8 mol/L aqueous sodium hydroxide solution (2.5 mL) at OC, and the reaction mixture was stirred at the same temperature for 30 min. Water was added to the 15 reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel 20 column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a white solid (yield 1.06 g, 54%). 1 H-NMR (CDCl 3 )5: 2.56 (3H, s), 6.58-6.59 (1H, m), 6.65-6.67 (1H, m), 8.52 (1H, brs), 9.89 (1H, s). Reference Example 53 25 2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde By a similar reaction as in Reference Example 44 and using 2-methyl-lH-pyrrole-3-carbaldehyde (1.10 g), sodium hydride (60% in oil, 1.20 g), 15-crown-5 (6.0 mL) and pyridin 3-ylsulfonyl chloride hydrochloride (3.22 g), the title 30 compound was obtained as white crystals (yield 1.10 g, 44%). 'H-NMR (CDCl 3 )5: 2.66 (3H, s), 6.68 (1H, d, J=3.9 Hz), 7.34 (1H, d, J=3.9 Hz), 7.51-7.55 (1H, m), 8.09-8.13 (1H, m), 8.89 8.91 (1H, m), 9.10-9.11 (1H, m), 9.90 (1H, s). Reference Example 54 35 5-bromo-2-methyl-l-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 81 carbaldehyde To a solution of 2-methyl-1-(pyridin-3-ylsulfonyl)-1H pyrrole-3-carbaldehyde (974 mg) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (1.17 g) at OC, and the 5 mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and 10 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as white crystals (yield 675 mg, 53%). H-NNR (CDCl 3 )S: 2.89 (3H, s), 6.18 (1H, s), 7.53-7.57 (1H, m), 15 8.21-8.26 (1H, m), 8.91-8.93 (1H, m), 9.17-9.18 (1H, m), 9.92 (1H, s). Reference Example 55 5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde Under an argon atmosphere, 5-phenyl-1H-pyrrole-3 20 carbaldehyde (342 mg) was dissolved in absolute tetrahydrofuran (20 mL) and sodium hydride (60% in oil, 240 mg) was added while stirring at room temperature. After stirring at the same temperature for 15 min, 15-crown-5 (1.21 mL) was added, and the mixture was further stirred at the same 25 temperature for 15 min. Pyridin-3-ylsulfonyl chloride hydrochloride (642 mg) was added, and the mixture was further stirred at the same temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and 30 saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-+1:1) to give the title compound as a brown solid (yield 470 mg, 75%). 35 1 H-NMR (CDCl 3 )5: 6.60 (1H, d, J=1.8 Hz), 7.15-7.19 (2H, m), 82 7.25-7.37 (3H, m), 7.42-7.48 (IH, M), 7.53-7.57 (1H, m), 8.13 (iH, d, J=1.8 Hz), 8.49-8.50 (1H, m), 8.74-8.76 (1H, m), 9.90 (1H, s). Reference Example 56 5 1-[(6-methoxypyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3 carbaldehyde Under an argon atmosphere, 5-phenyl-1H-pyrrole-3 carbaldehyde (171 mg) was dissolved in absolute tetrahydrofuran (20 mL), and sodium hydride (60% in oil, 200 10 mg) was added at room temperature while stirring. After stirring at the same temperature for 15 min, 15-crown-5 (1.01 mL) was added, and the mixture was further stirred at the same temperature for 15 min. 6-Methoxypyridin-3-ylsulfonyl chloride (623 mg) was added, and the mixture was stirred at the same 15 temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified 20 by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1->1:1) to give the title compound as an oil (yield 59 mg, 17%). 'H-NMR (CDCl 3 )5: 3.95 (3H, s), 6.59-6.62 (2H, m), '7.19-7.44 (6H, m), 8.08-8.10 (2H, m), 9.88 (1H, s). 25 Reference Example 57 1-(6-chloropyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrole-3 carbaldehyde Under an argon atmosphere, 5-phenyl-1H-pyrrole-3 carbaldehyde (514 mg) was dissolved in absolute 30 tetrahydrofuran (15 mL), and sodium hydride (60% in oil, 180 mg) was added at room temperature while stirring. After stirring at the same temperature for 15 min, 15-crown-5 (0.90 mL) was added, and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridin-3-ylsulfonyl chloride 35 (827 mg) was added, and the mixture was further stirred at the 83 same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was 5 evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-7:3) to give the title compound as an oil (yield 762 mg, 73%). -H-NMR (CDCl 3 )5: 6.62 (1H, s), 7.19-7.49 (7H, m), 8.09 (1H, s), 10 8.24-8.26 (1H, m), 8.90 (1H, s). Reference Example 58 1-(2-chloropyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrole-3 carbaldehyde By a reaction under similar conditions as in Reference 15 Example 55 and using 5-phenyl-lH-pyrrole-3-carbaldehyde (514 mg), sodium hydride (60% in oil, 180 mg), 15-crown-5 (0.90 mL) and 2-chloro-3-pyridinesulfonyl chloride (716 mg), the title compound was obtained as an amorphous form (yield 716 mg, 69%). 20 1 H-NMR (CDCl 3 )6: 6.64 (1H, s), 6.70-6.90 (1H, m), 7.05-7.08 (2H, m), 7.15-7.18 (2H, m), 7.26-7.32 (1H, m), 7.55-7.59 (1H, m), 8.26 (1H, s), 8.44-8.46 (1H, m), 9.94 (1H, s). Reference Example 59 1-(2-chloropyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrole-3 25 carbaldehyde By a reaction under similar conditions as in Reference Example 55 and using 5-phenyl-lH-pyrrole-3-carbaldehyde (342 mg), sodium hydride (60% in oil, 120 mg), 15-crown-5 (0.60 mL) and 2-chloro-5-pyrimidinesulfonyl chloride (554 mg), the title 30 compound was obtained as a yellow solid (yield 390 mg, 56%). 'H-NMR (CDCl 3 )S: 6.68 (1H, s), 7.22-7.26 (2H, m), 7.39-7.52 (3H, m), 8.09 (1H, s), 8.35 (2H, s), 9.91 (1H, s). Reference Example 60 1-[(6-chloro-5-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H 35 pyrrole-3-carbaldehyde 84 By a reaction under similar conditions as in Reference Example 55 and using 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and 6-chloro-5-methylpyridine-3-sulfonyl chloride (270 mg), 5 the title compound was obtained as a solid (yield 244 mg, 68%). H-NMR (CDCl 3 )5: 2.27 (3H, s), 6.62 (1H, s), 7.20-7.26 (3H, m), 7.35-7.49 (3H, m), 8.09 (1H, s), 8.13 (1H, m), 9.90 (1H, s). Reference Example 61 10 2-methyl-5-phenyl-l-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carbaldehyde A solution (15 mL) of ethyl 2-methyl-5-phenyl-l-(pyridin 3-ylsulfonyl)-1H-pyrrole-3-carboxylate (980 mg) in tetrahydrofuran was cooled to -780C, a 1.5 mol/L solution (5.3 15 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min., and the mixture was warmed to 00C over 2 hr. Water (100 mL) and ethyl acetate (20 iL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through celite, and the organic 20 layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile solution (25 mL), tetra-n-propylammonium perruthenate (93 mg), N methylmorpholine N-oxide hydrate (466 mg) and molecular sieves 25 4A powder (500 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (30 mL) was added to the residue. The mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate 3o was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane ethyl acetate=19:1->1:1) to give the title compound as a yellow oil (yield 235 mg, 27%). 1 H-NMR (CDCl 3 )5: 2.93 (3H, s), 6.51 (1H, s), 7.18-7.42 (6H,- m), 35 7.59-7.64 (1H, m), 8.60 (1H, s), 8.77-8.79 (1H, m), 10.03 (1H, 85 s). Reference Example 62 1-[(2-methyl-5-pyrimidine)sulfonyl]-5-phenyl-lH-pyrrole-3 carbaldehyde 5 Under a nitrogen atmosphere, a solution of ethyl 1-[(2 methyl-5-pyrimidine)sulfonyl]-5-phenyl-lH-pyrrole-3 carboxylate (280 mg) in tetrahydrofuran (20 mL) was cooled to -780C, a 1.5 mol/L solution (3.0 mL) of diisobutylaluminum hydride in toluene was added while stirring. After stirring at 10 the same temperature for 15 min, the mixture was allowed to warm to -400C over 30 min. Water (50 mL) was added, and after stirring at the same temperature for 5 min, the mixture was allowed to warm to 00C over 10 min. Ethyl acetate (30 mL) was added, and after stirring at the same temperature for 15 min, 1.5 the mixture was stirred at room temperature for 20 min. A gel like mixture was filtered through celite, and celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced 20 pressure. The residue was dissolved in tetrahydrofuran (50 mL), manganese dioxide (75% chemically treated product, 3.0 g) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was 25 concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane ethyl acetate=19:1->1:1) to give the title compound as a pale yellow solid (yield 150 mg, 61%). 1 H-NMR (CDCl 3 )S: 2.78 (3H, s), 6.64 (1H, s), 7.21-7.26 (2H, m), 3o 7.36-7.51 (3H, m), 8.10 (1H, s), 8.40 (2H, s), 9.90 (1H, s). Reference Example 63 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrole-3 carbaldehyde To a solution (96 mL) of 5-(2-fluorophenyl)-lH-pyrrole-3 35 carbaldehyde (475 mg) in tetrahydrofuran was added sodium 86 hydride (60% in oil, 503 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (2.77 g) was added dropwise and the mixture was stirred for 30 min. Pyridine-3 sulfonyl chloride hydrochloride (1.35 g) was added, and the 5 mixture was further stirred for 3 hr. The reaction mixture was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified 10 by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3-+2:3) and crystallized from diisopropyl ether-ethyl acetate (4:1) to give the title compound as colorless crystals (yield 680 mg, 82%). 1 H-NMR (CDCl 3 )5: 6.68 (1H, d, J=1.8 Hz), 6.99-7.05 (1H, m), 15 7.16-7.19 (2H, m), 7.35-7.39 (1H, m), 7.45-7.51 (1H, m), 7.69 7.73 (1H, m), 8.14 (1H, d, J=1.8 Hz), 8.58-8.59 (1H, m), 8.81 8.83 (1H, m), 9.91 (1H, s). Reference Example 64 1-(pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl]-1H 20 pyrrole-3-carbaldehyde To a solution (36 mL) of 5-[2-(trifluoromethyl)phenyll 1H-pyrrole-3-carbaldehyde (240 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 201 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (1.11 g) 25 was added dropwise and the mixture was stirred for 30 min. Pyridine-3-sulfonyl chloride hydrochloride (537 mg) was added, and the mixture was further stirred for 3 hr. The reaction mixture was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with 3o saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1->2:3) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 380 mg, 35 about 100%). 87 1 H-NMR (CDCl 3 )5: 6.69 (1H, d, J=1.8 Hz), 7.34-7.38 (1H, m), 7.44-7.48 (1H, m), 7.61-7.69 (4H, m), 8.16 (1H, d, J=1.8 Hz), 8.45 (1H, d, J=2.4 Hz), 8.81 (1H, m), 9.91 (1H, s). Reference Example 65 5 4-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carbaldehyde 4-Methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 60 mg) was added and the mixture was stirred at room 10 temperature for 15 min. 15-Crown-5 (0.30 mL) was added and the mixture was further stirred at the same temperature for 15 min. 3-Pyridinesulfonyl chloride hydrochloride (231 mg) was added and the reaction mixture was stirred at room temperature for 1 hr. Water was added, and the mixture was extracted with 15 ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-.1:1) to give the title compound as a colorless 20 solid (yield 172 mg, 53%). 1 H-NMR (CDCl 3 )6: 2.03 (3H, s), 7.01-7.04 (2H, m), 7.26-7.55 (5H, m), 8.07 (1H, s), 8.47 (1H, m), 8.75-8.78 (1H, m), 9.97 (1H, s). Reference Example 66 25 4-methyl-5-phenyl-l-(pyridin-2-ylsulfonyl)-1H-pyrrole-3 carbaldehyde By a reaction under similar conditions as in Reference Example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3 carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15 3o crown-5 (0.30 mL) and 2-pyridinesulfonyl chloride (231 mg) instead of 3-pyridinesulfonyl chloride hydrochloride, the title compound was obtained as an amorphous form (yield 262 mg,.80%). 1 H-NMR (CDCls)5: 2.03 (3H, s), 6.92-6.95 (2H, m), 7.21-7.49 35 (5H, m), 7.65-7.69 (1H, m), 8.14 (1H, s), 8.64-8.65 (1H, m), 88 9.98 (1H, s). Reference Example 67 1-[(1,2-dimethyl-lH-imidazol-4-yl)sulfonyl]-4-methyl-5-phenyl 1H-pyrrole-3-carbaldehyde 5 By a reaction under similar conditions as in Reference Example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3 carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15 crown-5 (0.30 mL) and (1,2-dimethyl-1H-imidazol-4-yl)sulfonyl chloride (253 mg), the title compound was obtained as a 10 colorless solid (yield 294 mg, 86%). H-NMR (CDCl 3 )S: 2.05 (3H, s), 2.33 (3H, s), 3.40 (3H, s), 6.48 (1H, s), 7.11-7.14 (2H, m), 7.26-7.41 (3H, m), 8.08 (1H, s), 9.93 (1H, s). Reference Example 68 1.5 1-[(5-chloro-1,3-dimethyl-lH-pyrazol-4-yl)sulfonyll-4-methyl 5-phenyl-1H-pyrrole-3-carbaldehyde By a reaction under similar conditions as in Reference Example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3 carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15 20 crown-5 (0.30 mL) and (5-chloro-1,3-dimethyl-1H-pyrazol-4 yl)sulfonyl chloride (298 mg), the title compound was obtained as an oil (yield 379 mg, about 100%). 'H-NMR (CDCl 3 )8: 1.74 (3H, s), 2.04 (3H, s), 3.69 (3H, s), 7.04-7.07 (2H, m), 7.28-7.38 (3H, m), 8.09 (1H, s), 9.96 (1H, 25 S). Reference Example 69 1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methyl-5-phenyl 1H-pyrrole-3-carbaldehyde By a reaction under similar conditions as in Reference 30 Example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3 carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15 crown-5 (0.30 mL) and (2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl chloride (275 mg), the title compound was obtained as an oil (yield 27.8 mg, 8%). 35 H-NMR (CDCl 3 )S: 2.05 (3H, s), 2.10 (3H, s), 2.59 (3H, s), 89 7.07-7.10 (2H, m), 7.31-7.40 (3H, m), 8.02 (1H, s), 9.96 (1H, s). Reference Example 70 5-(2-fluorophenyl)-4-methyl-1-(pyridin-3-ylsulfonyl)-lH 5 pyrrole-3-carbaldehyde By a similar operation as in Reference Example 65 and using 5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carbaldehyde (301 mg), sodium hydride (60% in oil, 179 mg), 15-crown-5 (0.88 mL) and pyridin-3-ylsulfonyl chloride hydrochloride (476 20 mg), the title compound was obtained as white crystals (yield 440 mg, 87%). H-NMR (CDCl 3 )5: 2.02 (3H, s), 6.98-7.04 (1H, m), 7.13-7.24 (2H, m), 7.33-7.38 (1H, m), 7.43-7.51 (1H, m), 7.65-7.69 (1H, m), 8.09 (1H, s), 8.54-8.55 (1H, m), 8.80-8.82 (1H, m), 9.98 15 (1H, s). Reference Example 71 1- [5-bromo-1- (phenylsulfonyl) -1H-pyrrol-3-yl] -N methylmethanamine To a solution (60 mL) of 5-bromo-l-(phenylsulfonyl)-H 20 pyrrole-3-carbaldehyde (3.5 g) in methanol were added methylammonium chloride (7.5 g) and sodium cyanoborohydride (2.4 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution 25 was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil 30 (yield 4.4 g, about 100%). 1 H-NMR (CDCl 3 )5: 2.47 (3H, s), 2.98 (1H, brs), 3.66 (2H, s), 6.35 (1H, d, J=2.4 Hz), 7.51-7.57 (3H, m), 7.61-7.68 (1H, m), 7.9.3-7.97 (2H, m). Reference Example 72 35 tert-butyl {[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3 90 yl]methyl}methylcarbamate To a solution of 1-[5-bromo-1-(phenylsulfonyl)-1H-pyrrol 3-yl]-N-methylmethanamine (4.4 g) in ethyl acetate (60 mL) was added di-tert-butyl bicarbonate (2.8 mL), and the mixture was 5 stirred at room temperature for 14 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium 10 sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless oil (yield 3.4 g, 73%). 'H-NMR (CDCl 3 )6: 1.48 (9H, s), 2.79 (3H, brs), 4.17 (2H, brs), 15 6.24 (1H, brs), 7.35 (1H, brs), 7.51-7.57 (2H, m), 7.62-7.68 (1H, m), 7.90-7.94 (2H, m). Reference Example 73 tert-butyl [(5-bromo-lH-pyrrol-3-yl)methyllmethylcarbamate tert-Butyl {[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3 20 yl]methyl}methylcarbamate (1.0 g) was dissolved in a mixed solvent of tetrahydrofuran (15 mL) and methanol (5 mL), and 8 mol/L aqueous sodium hydroxide solution (1.5 mL) was added dropwise at not more than 100C. After stirring at the same temperature for 4 hr, water was added to the residue and the 25 mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=9:1->4:1) to give the title 3o compound as a pale-yellow oil (yield 410 mg, 61%). 1H-NMR (CDCl 3 )S: 1.48 (9H, s), 2.79 (3H, s), 4.17 (2H, s), 6.09 (1H, brs), 6.64 (1H, brs), 8.07 (1H, br). Reference Example 74 tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-l1H-pyrrol-3 35 yl]methyl}methylcarbamate 91 To a suspension (10 mL) of sodium hydride (60% in oil, 204 mg) in tetrahydrofuran was added a solution (3 mL) of tert-butyl [(5-bromo-lH-pyrrol-3-yl)methyllmethylcarbamate (410 mg) in N,N-dimethylformamide at OC, and 15-crown-5 (938 5 mg) and pyridin-3-ylsulfonyl chloride hydrochloride (456 mg) were added at the same temperature. After stirring at room temperature for 2 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate 20 solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1->3:1) to give the title compound as a pale-yellow powder (yield 522 mg, 85%). 15 1H-NMR (CDCl 3 )5: 1.47 (9H, s), 2.80 (3H, brs), 4.18 (2H, brs), 6.28 (1H, brs), 7.35 (1H, brs), 7.48-7.52 (1H, m), 8.18-8.22 (1H, m), 8.85-8.88 (1H, m), 9.12-9.13 (1H, m). Reference Example 75 tert-butyl {[1-(2-chloro-3-pyridinesulfonyl)-5-phenyl-lH 20 pyrrol-3-yllmethyl}methylcarbamate 1-(2-Chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrole-3 carbaldehyde (443 mg) was dissolved in absolute tetrahydrofuran (5 mL), a 2 mol/L solution (0.74 mL) of methylamine in tetrahydrofuran was added, and the mixture was 25 stirred at room temperature for 30 min. The reaction mixture was added to a solution of sodium borohydride (97 mg) in methanol (2.5 mL), and the mixture was stirred at the same temperature for 20 min. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous 30 sodium hydrogencarbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), di-tert-butyl bicarbonate (1.40 g), sodium hydrogencarbonate (0.54 g) and 35 water (13 mL) were added, and the mixture was stirred at room 92 temperature for 20 min. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate, and the solvent 5 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane ethyl acetate=19:1-+3:1) to give the title compound as a solid (yield 361 mg, 61%). 1 H-NMR (CDCl 3 )S: 1.47 (9H, s), 2.87 (3H, s), 4.29 (2H, s), 10 6.30-6.32 (lH, m), 6.95-7.00 (1H, m), 7.06-7.33 (5H, m), 7.51 7.56 (2H, m), 8.38-8.41 (1H, m). Reference Example 76 tert-butyl {[1-(6-chloro-5-methyl-3-pyridinesulfonyl)-5 phenyl-1H-pyrrol-3-yl]methylmethylcarbamate 15 1-[(6-Chloro-5-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H pyrrole-3-carbaldehyde (244 mg) was dissolved in absolute tetrahydrofuran (6.8 mL), a 2 mol/L solution (0.34 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was 20 added to a solution of sodium borohydride (51 mg) in methanol (3 mL), and the mixture was stirred at the same temperature for 3 min. di-tert-Butyl bicarbonate (654 mg) was added, and water (5 mL) and sodium hydrogencarbonate (420 mg) were added 3 min later. The mixture was further stirred at room 25 temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel 30 column chromatography (eluent: hexane-ethyl acetate=19:1->3:1) to give the title compound as an oil (yield 247 mg, 77%). 1 H-NMR (CDCl3)S: 1.47 (9H, s), 2.28 (3H, s), 2.82 (3H, s), 4.24-4.28 (2H, m), 6.15 (1H, s), 7.23-7.42 (7H, m), 8.15 (IH, s). 35 Reference Example 77 93 tert-butyl ({[1-(6-chloropyridin-3-yl)sulfonyl]-5-phenyl-1H pyrrol-3-yl}methyl)methylcarbamate 1-[(6-Chloropyridin-3-yl)sulfonyl]-5-phenyl-lH-pyrrole-3 carbaldehyde (1.27 g) was dissolved in absolute 5 tetrahydrofuran (20 mL), a 2 mol/L solution (2.1 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a solution of sodium borohydride (277 mg) in methanol (10 mL), and the mixture was stirred at the same 10 temperature for 20 min. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate. di-tert-Butyl bicarbonate (3.99 g) was added, and the solvent was evaporated 25 under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), sodium hydrogencarbonate (1.53 g) and water (36 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous 20 sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-+3:1) to give the title compound as a solid (yield 25 544 mg, 32%). 1 H-NMR (CDCl 3 )S: 1.47 (9H, s), 2.82 (3H, s), 4.23 (2H, s), 6.16 (1H, s), 7.23-7.49 (8H, m), 8.28 (1H, s). Reference Example 78 tert-butyl methyl({[1-(6-methylpyridin-3-yl)sulfonyl]-5 30 phenyl-lH-pyrrol-3-yl}methyl)carbamate Under an argon atmosphere, a mixture of tert-butyl ({[l (6-chloropyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3 yl}methyl)methylcarbamate (100 mg), methylboronic acid (14 mg), tetrakis(triphenylphosphine)palladium (25 mg), potassium 35 carbonate (90 mg) and dioxane (3 mL) was stirred at 80 0 C for 24 94 hr. Methylboronic acid (14 mg) and tetrakis(triphenylphosphine)palladium (25 mg) were added, and the mixture was stirred at 900C for 24 hr. Methylboronic acid (14 mg), tetrakis(triphenylphosphine)palladium (25 mg), 5 potassium carbonate (90 mg) and dioxane (2 mL) were added, and the mixture was stirred at 900C for 24 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium 10 sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1->1:1) to give the title compound as an oil (yield 85.8 mg, 36%). H-NMR (CDCl 3 )S: 1.46 (9H, s), 2.58 (3H, s), 2.81 (3H, s), 15 4.20-4.23 (2H, m), 6.13 (1H, s), 7.07-7.10 (1H, m), 7.24-7.42 (7H, m), 8.39 (1H, s) . Reference Example 79 tert-butyl methyl{[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-1H pyrrol-3-yl methyl}carbamate 20 Under an argon atmosphere, a suspension of tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3 yl]methyl}methylcarbamate (232 mg), 3-thienylboronic acid (138 mg), tetrakis(triphenylphosphine)palladium (31.3 mg) and sodium carbonate (175 mg) in 1,2-dimethoxyethane (10 mL) and 25 water (5 mL) was stirred at 1050C for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated 3o brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow oil (yield 189 mg, 81%). 35 1 H-NMR (CDCl 3 )S: 1.47 (9H, s), 2.82 (3H, brs), 4.22 (2H, brs), 95 6.17 (1H, brs), 7.04-7.06 (1H, m), 7.16-7.17 (1H, m), 7.25 7.32 (3H, m), 7.57-7.61 (1H, m), 8.56 (1H, d, J=2.4 Hz), 8.71 8.73 (1H, m). Reference Example 80 5 tert-butyl {[5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yllmethyl}methylcarbamate By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]methyl}methylcarbamate (300 mg), (4-fluorophenyl)boronic 10 acid (195 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 293 mg, 94%). H-NMR (CDCl 3 )5: 1.47 (9H, s), 2.81 (3H, brs), 4.22 (2H, brs), 6.12 (1H, brs), 7.00-7.06 (2H, m), 7.18-7.31 (4H, m), 7.56 15 7.60 (1H, m), 8.54-8.55 (1H, m), 8.73-8.75 (1H, m). Reference Example 81 tert-butyl methyl{[5-(2-methylphenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl methyl}carbamate By a similar operation as in Reference Example 79 and 20 using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-lH-pyrrol 3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 210 mg, 68%). More specifically, a 25 suspension of tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yllmethyl}methylcarbamate (300 mg), (2 methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water 30 (7.5 mL) was stirred at 1050C for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried 35 over anhydrous sodium sulfate, and concentrated under reduced 96 pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1->3:1) to give the title compound as a pale-yellow oil (yield 210 mg, 68%). 1 H-NMR (CDCl 3 )S: 1.47 (9H, s), 1.92 (3H, s), 2.84 (3H, brs), 5 4.26 (2H, brs), 6.07 (1H, d, J=1.2 Hz), 6.87-6.89 (1H, m), 7.09-7.19 (2H, m), 7.26-7.35 (3H, m), 7.58-7.62 (1H, m), 8.54 8.55 (1H, m), 8.75-8.77 (1H, m). Reference Example 82 tert-butyl {[5-(4-fluoro-2-methylphenyl)-1-(pyridin-3 10 ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]methyl}methylcarbamate (300 mg), (4-fluoro-2 methylphenyl)boronic acid (215 mg), 15 tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale yellow oil (yield 216 mg, 67%). 1 H-NMR (CDCl 3 )5: 1.47 (9H, s), 1.92 (3H, s), 2.84 (3H, brs), 4.25 (2H, brs), 6.05 (1H, br), 6.79-6.91 (3H, m), 7.30-7.35 20 (2H, m), 7.61-7.65 (1H, m), 8.58-8.59 (1H, m), 8.77-8.79 (1H, m). Reference Example 83 tert-butyl methyl{[5-(4-methyl-3-thienyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate 25 By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3 thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium 30 carbonate (222 mg), the title compound was obtained as a pale yellow oil (yield 200 mg, 64%) . More specifically, a suspension of tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl) lH-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3 thienyl)boronic acid (198 mg), 35 tetrakis(triphenylphosphine)palladium (40 mg) and sodium 97 carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 1050C for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl 5 acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1->3:1) to give lo the title compound as a pale-yellow oil (yield 200 mg, 64%). 1 H-NMR (CDCl 3 )6: 1.47 (9H, s), 1.81 (3H, s), 2.83 (3H, brs), 4.26 (2H, brs), 6.10 (1H, br), 6.90 (1H, br), 7.02-7.03 (1H, m), 7.26-7.35 (2H, m), 7.61-7.65 (1H, m), 8.58-8.59 (1H, m), 8.75-8.77 (1H, m). 15 Reference Example 84 tert-butyl {[5-(3-cyanophenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl methyl}methylcarbamate By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-1H-pyrrol 20 3-yl]methyl}methylcarbamate (300 mg), (3-cyanophenyl)boronic acid (205 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 298 mg, 94%). 'H-NMR (CDCl 3 )6: 1.47 (9H, s), 2.81 (3H, brs), 4.22 (2H, brs), 25 6.21 (1H, br), 7.31-7.35 (2H, m), 7.46-7.69 (6H, m), 8.56 (1H, d, J=1.8 Hz), 8.76-8.78 (1H, m). Reference Example 85 tert-butyl {[5-(2-chlorophenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl methyl}methylcarbamate 30 By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]methyl}methylcarbamate (300 mg), (2-chlorophenyl)boronic acid (218 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained 35 as a pale-blue oil (yield 171 mg, 53%). 98 1H-NMR (CDCl 3 )6: 1.47 (9H, s), 2.84 (3H, brs), 4.26 (2H, brs), 6.20 (1H, d, J=1.8 Hz), 7.26-7.36 (6H, m), 7.65-7.71 (1H, m), 8.58-8.59 (1H, m), 8.75-8.79 (1H, m). Reference Example 86 5 tert-butyl {[5-(2,4-difluorophenyl)-lH-pyrrol-3 yl]methyl}methylcarbamate By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-lH-pyrrol 3-yl]methyl}methylcarbamate (300 mg), (2,4 10 difluorophenyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 113 mg, 50%). 1 H-NMR (CDCl 3 )6: 1.50 (9H, s), 2.84 (3H, brs), 4.30 (2H, brs), 15 6.49 (1H, br), 6.78-6.92 (3H, m), 7.48-7.58 (1H, m), 8.78 (1H, br). Reference Example 87 tert-butyl {[5-(2,5-difluorophenyl)-1H-pyrrol-3 yl methyl}methylcarbamate 20 By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-lH-pyrrol 3-yl]methyl}methylcarbamate (300 mg), (2,5 difluorophenyl)boronic acid (220 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium 25 carbonate (220 mg), the title compound was obtained as a colorless oil (yield 135 mg, 60%). 1 H-NMR (CDCl 3 )5: 1.50 (9H, s), 2.84 (3H, brs), 4.30 (2H, brs), 6.56 (1H, br), 6.77-6.85 (2H, m), 7.00-7.08 (1H, m), 7.20-7.26 (1H, m), 8.90 (1H, br). 30 Reference Example 88 tert-butyl {[5-(4-chloro-2-fluorophenyl)-lH-pyrrol-3 ylmethyl}methylcarbanate By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 35 3-yl]methyl}methylcarbamate (300 mg), (4-chloro-2 99 fluorophenyl)boronic acid (243 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 127 mg, 54%). 5 1 H-NMR (CDCl 3 )5: 1.50 (9H, s), 2.84 (3H, s), 4.30 (2H, s), 6.55 (1H, br), 6.80 (1H, br), 7.11-7.15 (2H, m), 7.46-7.52 (1H, m), 8.82 (1H, br). Reference Example 89 tert-butyl {[5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl) 10 1H-pyrrol-3-yl]methyl}methylcarbamate By a similar operation as in Reference Example 44 and using tert-butyl {[5-(2,4-difluorophenyl)-1H-pyrrol-3 yl]methyl}methylcarbamate (113 mg), sodium hydride (60% in oil, 51 mg), 15-crown-5 (0.21 mL) and pyridine-3-ylsulfonyl 15 chloride hydrochloride (113 mg), the title compound was obtained as a pale-yellow oil (yield 110 mg, 68%). 'H-NMR (CDCl 3 )S: 1.46 (9H, s), 2.82 (3H, brs), 4.24 (2H, brs), 6.19 (1H, br), 6.77-6.92 (2H, m), 7.11-7.19 (1H, m), 7.33-7.37 (2H, m), 7.68-7.72 (1H, m), 8.62 (1H, d, J=2.4 Hz), 8.77-8.79 20 (1H, m) Reference Example 90 tert-butyl {[5-(2,5-difluorophenyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl methyl}methylcarbamate By a similar operation as in Reference Example 44 and 25 using tert-butyl {[5-(2,5-difluorophenyl)-1H-pyrrol-3 yllmethyl}methylcarbamate (135 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.25 mL) and pyridin-3-ylsulfonyl chloride hydrochloride (135 mg), the title compound was obtained as a colorless oil (yield 105 mg, 54%). 30 1 H-NMR (CDCl 3 )5: 1.50 (9H, s), 2.82 (3H, s), 4.23 (2H, brs), 6.24 (1H, br), 6.89-7.13 (4H, m), 7.33-7.39 (2H, m), 7.71-7.75 (1H, m), 8.67 (1H, d, J=2.4 Hz), 8.78-8.80 (1H, m). Reference Example 91 tert-butyl {[5-(4-chloro-2-fluorophenyl)-1-(pyridin-3 35 ylsulfonyl)-1H-pyrrol-3-ylImethyl}methylcarbamate 100 By a similar operation as in Reference Example 44 and using tert-butyl {[5-(4-chloro-2-fluorophenyl)-lH-pyrrol-3 yllmethyl}methylcarbamate (127 mg), sodium hydride (60% in oil, 54 mg), 15-crown-5 (0.22 mL) and pyridin-3-ylsulfonyl 5 chloride hydrochloride (120 mg), the title compound was obtained as a colorless oil (yield 103 mg, 57%). 'H-NMR (CDCl 3 )6: 1.46 (9H, s), 2.81 (3H, s), 4.23 (2H, brs), 6.21 (1H, brs), 7.08-7.15 (4H, m), 7.32-7.38 (2H, m), 7.69 7.73 (1H, m), 8.64 (1H, d, J=2.4 Hz), 8.77-8.79 (1H, m). 10 Reference Example 92 tert-butyl {[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yllmethyl}methylcarbamate By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 15 3-yl]methyl}methylcarbamate (300 mg), (3-fluorophenyl)boronic acid (195 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 280 mg, 90%). 1 H-NNR (CDCl 3 )S: 1.47 (9H, s), 2.81 (3H, brs), 4.22 (2H, brs), 20 6.16 (1H, brs), 6.93-7.11 (3H, m), 7.27-7.32 (3H, m), 7.59 7.63 (1H, m), 8.58 (1H, d, J=2.1 Hz), 8.73-8.75 (1H, m). Reference Example 93 tert-butyl {[5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl methyl}methylcarbamate 25 5-Bromo-2-methyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3 carbaldehyde (565 mg) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), a 40% solution (1.5 mL) of methylamine methanol was added at room temperature and the mixture was stirred for 30 min. Sodium borohydride (130 mg) was added to 3o the reaction mixture at room temperature and the mixture was stirred for 15 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was 35 washed with saturated aqueous sodium hydrogencarbonate 101 solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (6 mL), di-tert-butyl bicarbonate (0.45 mL) was added, and the mixture 5 was stirred at room temperature for 1 hr. To the reaction mixture was added 1 mol/L hydrochloric acid (10 mL), and the mixture was further stirred for 15 min. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. 10 The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1-+1:1) 25 to give a mixture of the title compound and 5-bromo-2-methyl 1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde. The mixture was dissolved in tetrahydrofuran (5 mL), a 2 mol/L solution (4 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 12 hr. To 20 the reaction mixture was added a solution of sodium borohydride (131 mg) in methanol (1 mL), and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was 25 extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (6 mL), di-tert-butyl bicarbonate 30 (0.45 mL) was added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate 35 solution, water and saturated brine, dried over anhydrous 102 sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a yellow oil (yield 384 mg, 50%). 5 'H-NMR (CDCl 3 )5: 1.46 (9H, s), 2.49 (3H, s), 2.71 (3H, brs), 4.15 (2H, brs), 6.24 (1H, brs), 7.47-7.52 (1H, m), 8.13-8.17 (1H, m), 8.84-8.86 (1H, m), 9.07-9.08 (1H, m). Reference Example 94 2-bromo-1-(2,6-difluorophenyl)ethanone 10 To a solution of 1-(2,6-difluorophenyl)ethanone (10.0 g) in diethyl ether (50 mL) was added anhydrous aluminum chloride (86 mg) and the mixture was stirred for 5 min. Bromine (3.3 mL) was added dropwise at 10-150C. After stirring at room temperature for 2 hr, the mixture was poured into water, and 25 the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 15.2 g, about 100%). 20 1 H-NMR (CDCl 3 )5: 4.37 (2H, s), 6.97-7.04 (2H, m), 7.43-7.53 (1H, m). Reference Example 95 ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate To a solution of ethyl cyanoacetate (7.24 g) and 25 diisopropylethylamine (19.9 g) in tetrahydrofuran (30 mL) was added dropwise a solution of 2-bromo-l-(2,6 difluorophenyl)ethanone (15.16 g) in tetrahydrofuran (15 mL) at 10-150C. The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained 30 filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water, 1 mol/L hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel 35 column chromatography (eluent: hexane-ethyl acetate=4:1->3:2) 103 to give the title compound as a pale-green oil (yield 13.8 g, 81%). 'H-NMR (CDCl 3 )S: 1.35 (3H, t, J=7.1 Hz), 3.44-3.53 (1H, m), 3.63-3.72 (1H, m), 4.13-4.18 (1H, m), 4.31 (2H, q, J=7.1 Hz), 5 6.95-7.05 (2H, m), 7.44-7.54 (1H, m). Reference Example 96 methyl 2-cyano-4-(4-cyclohexylphenyl)-4-oxobutanoate 4-Cyclohexylacetophenone (10.0 g) was dissolved in chloroform (30 mL) and diethyl ether (30 mL), and bromine 10 (8.70 g) was slowly added dropwise. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hr, diluted with water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced 1.5 pressure to give crude 2-bromo-1-(5-cyclohexylpyridin-2 yl)ethanone (15.8 g) as an oil. This was dissolved in tetrahydrofuran (20 mL), and added dropwise to a mixture of methyl cyanoacetate (4.95 g), diisopropylethylamine (16.2 g) and tetrahydrofuran (50 mL). The reaction mixture was stirred 20 at room temperature for 20 hr, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was 25 purified by silica gel column chromatography (eluent: hexane ethyl acetate=4:1->3:1) to give the title compound as an oil (yield 12.1 g, 82%). 'H-NMR (CDCl 3 )S: 1.20-1.51 (5H, m), 1.70-1.90 (5H, m), 2.51 2.64 (1H, m), 3.47-3.73 (1H, m), 3.58-3.88 (1H, m), 3.85 (3H, 30 s), 4.09-4.19 (1H, m), 7.32 (2H, d, J=8.1 Hz), 7.89 (2H, d, J=8.1 Hz). Reference Example 97 ethyl 2-chloro-5-(2,6-difluorophenyl)-lH-pyrrole-3-carboxylate A solution (14 mL) of ethyl 2-cyano-4-(2,6 35 difluorophenyl)-4-oxobutanoate (13.83 g) in ethyl acetate was 104 added dropwise to 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) at 10-150C. The mixture was stirred at room temperature for 12 hr, and concentrated under reduced pressure. The residue was purified by silica gel column 5 chromatography (eluent: hexane-ethyl acetate=9:1-+8:2) to give the title compound as yellow crystals (yield 10.0 g, 68%). 1 H-NMR (CDCl 3 )S: 1.38 (3H, t, J=7.2 Hz), 4.34 (2H, q, J=7.2 Hz), 6.95-7.04 (2H, m), 7.14-7.23 (2H, m), 9.20 (1H, br). Reference Example 98 10 methyl 2-chloro-5-(4-cyclohexylphenyl)-1H-pyrrole-3 carboxylate 14% Hydrogen chloride - 1,4-dioxane solution (50 mL) was added to methyl 2-cyano-4-(4-cyclohexylphenyl)-4-oxobutanoate (12.1 g) and the mixture was stirred at room temperature for 8 15 hr and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether and collected by filtration to give a nearly 20 1:1 mixture (3.41 g) of the title compound and methyl 2-amino 5-(4-cyclohexylphenyl)-3-furoate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane ethyl acetate=7:2) to give the title compound as crystals 25 (yield 0.64 g, 5%). H-NMR (CDC1 3 )S: 1.22-1.48 (5H, m), 1.71-1.91 (5H, m), 2.46 2.58 (1H, m), 3.86 (3H, s), 6.81 (1H, d, J=3.2 Hz), 7.23 (2H, d, J=8.3 Hz), 7.36 (2H, d, J=8.3 Hz), 8.67 (1H, brs). Reference Example 99 3o methyl 2-chloro-4-fluoro-5-phenyl-lH-pyrrole-3-carboxylate To a suspension of methyl 2-chloro-5-phenyl-1H-pyrrole-3 carboxylate (4.66 g) synthesized from methyl cyanoacetate and phenacyl bromide in the same manner as in Reference Example 95 and Reference Example 97 in acetonitrile (200 mL) was added 35 2,6-dichloro-N-fluoropyridinium triflate (6.26 g) over 10 min 105 under ice-cooling. The reaction mixture was stirred at the same temperature for 2 hr and at room temperature for 2 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, 5 and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1->7:3) to give the title compound as a pale-yellow solid (yield 815 10 mg, 16%). More specifically, to a solution of methyl cyanoacetate (41 g) and diisopropylethylamine (117 g) in tetrahydrofuran (2600 mL) was added dropwise a solution of phenacyl bromide (75 g) in tetrahydrofuran (370 mL). The mixture was stirred at room temperature for 12 hr. The 15 reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced 20 pressure. The residue was washed with diethyl ether to give methyl 2-cyano-4-phenyl-4-oxobutanoate as a brown oil (yield 77.4 g, 95%). To a solution (125 mL) of ethyl 2-cyano-4-(2,6 difluorophenyl)-4-oxobutanoate (25 g) in ethyl acetate was added dropwise 4 mol/L hydrogen chloride-ethyl acetate 25 solution (25 mL). The mixture was stirred at room temperature for 18 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over 30 anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give methyl 2-chloro-5-phenyl-lH-pyrrole-3-carboxylate as colorless crystals (yield 10.0 g, 37%). The title compound was synthesized from the thus-obtained methyl 2-chloro-5-phenyl 35 1H-pyrrole-3-carboxylate. 106 1 H-NMR (CDCl 3 )5: 3.90 (3H, s), 7.26-7.32 (1H, m), 7.40-7.60 (4H, m) , 8.29 (1H, br) . Reference Example 100 ethyl 5-(2,6-difluorophenyl)-lH-pyrrole-3-carboxylate 5 To a solution of ethyl 2-chloro-5-(2,6-difluorophenyl) 1H-pyrrole-3-carboxylate (9.82 g) in ethanol (200 mL) was added 10% palladium carbon (50% containing water, 4.91 g), and the mixture was stirred under a hydrogen atmosphere at 400C for 72 hr. The reaction mixture was filtered, and the filtrate was 10 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as colorless crystals (yield 3.80 g, 24%). 'H-NMR (CDCl 3 )5: 1.37 (3H, t, J=7.2 Hz), 4.32 (2H, q, J=7.2 15 Hz), 6.94-7.04 (2H, m), 7.11-7.21 (1H, m), 7.24-7.27 (1H, m), 7.54-7.55 (1H, m), 9.37 (1H, br). Reference Example 101 methyl 5-(4-cyclohexylphenyl)-lH-pyrrole-3-carboxylate To a solution of a nearly 1:1 mixture (3.41 g) of methyl 20 2-chloro-5-(4-cyclohexylphenyl)-lH-pyrrole-3-carboxylate and methyl 2-amino-5-(4-cyclohexylphenyl)-3-furoate in methanol (30 mL) and ethyl acetate (10 mL) was added 10% palladium carbon (50% containing water, 0.34 g), and the mixture was stirred under a hydrogen atmosphere at 500C for 14 hr. The 25 reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:1->2:1) to give the title compound as crystals (yield 1.25 g, 41%). 30 H-NMR (CDCl 3 )8: 1.19-1.50 (5H, m), 1.73-1.93 (5H, m), 2.43 2.57 (1H, m), 3.84 (3H, s), 6.86 (1H, s), 7.24 (2H, d, J=8.3 Hz), 7.41 (2H, d, J=8.3 Hz), 7.45 (1H, dd, J=3.0, 1.7 Hz), 8.73 (1H, brs). Reference Example 102 35 methyl 4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate 107 Methyl 2-chloro-4-fluoro-5-phenyl-1H-pyrrole-3 carboxylate (0.92 mg), 10% palladium carbon (50% containing water, 0.20 g) and triethylamine (0.56 mL) were suspended in methanol (30 mL), and the mixture was stirred under a hydrogen 5 atmosphere at room temperature for 2 hr. The reaction mixture was filtered through celite, and the insoluble material was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-l1:1) io to give the title compound as a colorless solid (yield 0.69 g, 87%). 1 H-NMR (CDCl 3 )8: 3.87 (3H, s), 7.24-7.31 (2H, m), 7.39-7.46 (2H, m), 7.51-7.54 (2H, m), 8.32 (1H, br). Reference Example 103 25 [5-(2,6-difluorophenyl)-lH-pyrrol-3-yllmethanol A solution (35 mL) of ethyl 5-(2,6-difluorophenyl)-1H pyrrole-3-carboxylate (3.35 g) in tetrahydrofuran was cooled to -500C, and a 1.5 mol/L solution (30 mL) of diisobutylaluminum hydride in toluene was added dropwise by 20 small portions. The mixture was stirred at the same temperature for 1 hr, water was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, celite and anhydrous magnesium sulfate were added and the mixture was 25 further stirred for 15 min. The suspension was filtrated, and the obtained filtrate was concentrated under reduced pressure to give the title compound as pale-red crystals (yield 2.70 g, 97%). 1 H-NMR (CDCl 3 )5: 1.46 (1H, br), 4.64 (2H, s), 6.88-7.02 (4H, 30 m), 7.06-7.16 (1H, m), 9.07 (1H, br). Reference Example 104 [5-(4-cyclohexylphenyl)-1H-pyrrol-3-yl methanol To a solution of methyl 5-(4-cyclohexylphenyl)-1H pyrrole-3-carboxylate (3.0 g) in absolute tetrahydrofuran (40 35 mL) was added dropwise a 1.5 mol/L solution (21.0 mL) of 108 diisobutylaluminum hydride in toluene at -780C. The mixture was further stirred at the same temperature for 2 hr. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was diluted with ethyl acetate. The insoluble material 5 was filtered off through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl 10 acetate=1:1) to give the title compound as crystals (yield 1.07 g, 40%). 1 H-NMR (CDCl 3 )S: 1.16-1.50 (5H, m), 1.69-1.93 (5H, m), 2.45 2.55 (1H, m), 4.60 (2H, s), 6.45-6.51 (1H, m), 6.81-6.86 (1H, m), 7.21 (2H, d, J=8.3 Hz), 7.39 (2H, d, J=8.3 Hz), 8.30 (1H, 15 br), 1H not detected. Reference Example 105 5-(2,6-difluorophenyl)-lH-pyrrole-3-carbaldehyde To a solution (26 mL) of [5-(2,6-difluorophenyl)-1H pyrrol-3-yl]methanol (2.56 g) in acetonitrile were added 20 tetra-n-propylammonium perruthenate (430 mg), N methylmorpholine N-oxide (2.15 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (60 mL) and filtered through celite. The filtrate was 25 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as pale-red crystals (yield 1.94 g, 77%). 1 H-NMR (CDCl 3 )8: 6.97-7.06 (2H, m), 7.16-7.24 (1H, m), 7.28 30 7.31 (1H, m), 7.56-7.58 (1H, m), 9.55 (1H, br), 9.88 (1H, s). Reference Example 106 5-(4-cyclohexylphenyl)-1H-pyrrole-3-carbaldehyde To a solution (35 mL) of [5-(4-cyclohexylphenyl)-1H pyrrol-3-yl]methanol (1.00 g) in acetonitrile were added 35 tetra-n-propylammonium perruthenate (115 mg), N 109 methylmorpholine N-oxide (0.60 g) and molecular sieves 4A powder (1.15 g) under ice-cooling. The mixture was stirred at room temperature for 1.5 hr, and the reaction mixture was suspended in ethyl acetate, and filtered through celite. The 5 filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as crystals (yield 0.53 g, 53%). H-NMR (CDCl 3 )S: 1.17-1.49 (5H, m), 1.70-1.95 (5H, m), 2.45 10 2.58 (1H, m), 6.89 (1H, s), 7.25 (2H, d, J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz), 7.47 (1H, s), 8.99 (1H, brs), 9.82 (1H, s). Reference Example 107 1H-pyrrole-3-carbaldehyde To a suspension of sodium hydride (13.7 g) in 15 tetrahydrofuran (450 mL) was added dropwise pyrrole (17.4 g) under ice-cooling. The reaction mixture was stirred at the same temperature for 1.5 hr, and triisopropylsilyl chloride (50.0 g) was added dropwise at the same temperature. The mixture was further stirred at below 100C for 1.5 hr, ice water 20 was added and the mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution of the residue (57.7 g) in dichloromethane (30 mL) was added at once to a suspension of (chloromethylene)dimethylammonium 25 chloride (36.5 g) in dichloromethane (500 mL) at 00C. The reaction mixture was refluxed for 30 min and cooled to 00C. The resulting solid was collected by filtration, and washed with diethyl ether. The obtained solid was dissolved in water (50 mL), a 1 mol/L aqueous sodium hydroxide solution (500 mL) 3o was added at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was extracted with chloroform and ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound 35 as pale-brown crystals (yield 9.4 g, 38%). 110 1 H-NMR (CDCl3)6: 6.68-6.70 (1H, m), 6.83-6.86 (1H, m), 7.45 7.47 (1H, m), 9.00-9.20 (1H, m), 9.82 (1H, s). Reference Example 108 2-chloro-2,2-difluoro-1-(2-methylphenyl)ethanone 5 Magnesium (flake, 6.2 g) was suspended in diethyl ether (10 mL), and iodine (small amount) was added and a solution of 2-bromotoluene (43.26 g) in diethyl ether (100 mL) were slowly added dropwise. After stirring at room temperature for 1 hr, the reaction mixture was added dropwise to a solution of 10 chlorodifluoroacetic acid (10.0 g) in diethyl ether (100 mL) at -100C, and the mixture was stirred at 00C for 1 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over 15 magnesium sulfate, and concentrated under reduced pressure. The residue was distilled under reduced pressure (boiling point: 81-820C/12-13 mmHg) to give the title compound as a pale-yellow oil (yield 4.9 g, 31%). 1 H-NMR (CDCl 3 )6: 2.54 (3H, s), 7.29-7.36 (2H, m), 7.47-7.53 20 (1H, m), 7.89-7.92 (1H, m) . Reference Example 109 2,2-difluoro-2-iodo-1-(2-methylphenyl)ethanone To a suspension of zinc (1.6 g) in acetonitrile (40 mL) were added trimethylsilyl chloride (3.1 mL) and 2-chloro-2,2 25 difluoro-l-(2-methylphenyl)ethanone (4.0 g), and the mixture was stirred at 550C for 3 hr. The reaction mixture was allowed to cool to room temperature, iodine (3.5 g) was added, and the mixture was further stirred for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl 30 ether. The extract was washed with aqueous sodium hydrogen sulfite solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane) to 35 give the title compound as a yellow oil (yield 2.6 g, 46%). 111 1H-NMR (CDC1 3 )S: 2.51 (3H, s), 7.26-7.35 (2H, m), 7.46-7.51 (1H, m), 7.91-7.94 (1H, m). Reference Example 110 2,2-difluoro-4-iodo-1-(2-methylphenyl)-4-trimethylsilylbutan 5 1-one Under a nitrogen atmosphere, to a mixture of tetrakis(triphenylphosphine)palladium (0.52 g) and vinyltrimethylsilane (1.9 mL) was added 2,2-difluoro-2-iodo-l (2-methylphenyl)ethanone (2.6 g), and the mixture was stirred lo at room temperature for 2 hr. Diethyl ether was added to the reaction mixture, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane) to give the title compound as a colorless oil 15 (yield 2.6 g, 74%). 1 H-NMR (CDCl 3 )S: 0.21 (9H, s), 2.50 (3H, s), 2.70-2.89 (2H, m), 3.19-3.24 (1H, m), 7.27-7.32 (2H, m), 7.42-7.48 (1H, m), 7.89 7.92 (1H, m). Reference Example 111 20 3-fluoro-2-(2-methylphenyl)-1H-pyrrole To a solution (20 mL) of 2,2-difluoro-4-iodo-1-(2 methylphenyl)-4-trimethylsilylbutan-1-one (2.5 g) in tetrahydrofuran was added 28% aqueous ammonia solution (6 mL), and the mixture was stirred at room temperature for 14 hr. The 25 reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (15 mL) and water (8 mL), and potassium fluoride (0.75 g) was added. The reaction 30 mixture was stirred at 600C for 3 hr, and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under 35 reduced pressure. The residue was purified by silica gel 112 column chromatography (eluent: hexane-ethyl acetate=20:1) to give the title compound as a pale-yellow oil (yield 0.87 g, 78%). 'H-NMR (CDCl 3 )5: 2.39 (3H, d, J=1.5 Hz), 6.06-6.08 (1H, m), 5 6.60-6.63 (1H, m), 7.19-7.33 (4H, m), 7.71 (1H, brs). Reference Example 112 5-bromo-1H-pyrrole-3-carbaldehyde A solution of 1H-pyrrole-3-carbaldehyde (19.1 g) in tetrahydrofuran (300 mL) was cooled to -700C, and a solution of 10 N-bromosuccinimide (35.8 g) in N,N-dimethylformamide (100 mL) was added dropwise. After stirring at the same temperature for 1 hr, the mixture was raised to -10Cc over 2 hr and further stirred for 30 min. Ice water was added to the reaction mixture at 0CC, and the mixture was allowed to warm to room 15 temperature and extracted with ethyl acetate. The extract was washed with 10% aqueous citric acid solution, 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crystals obtained as a residue were washed with 20 diisopropyl ether to give the title compound as colorless crystals (yield 17.7 g, 51%). 'H-NMR (CDCl 3 )6: 6.65-6.66 (1H, m), 7.37-7.38 (1H, m), 8.80 (1H, br), 9.70 (1H, s). Reference Example 113 25 5-(2-methylphenyl)-1H-pyrrole-3-carbaldehyde 5-Bromo-1H-pyrrole-3-carbaldehyde (100 mg), 2 methylphenylboronic acid (94 mg) and sodium carbonate (146 mg) were suspended in a mixed solvent of 1,2-dimethoxyethane (5 mL) and water (2 mL), and the mixture was sufficiently 3o degassed under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium (33 mg) was added, and the mixture was further degassed and refluxed at 1050C for 24 hr. The reaction mixture was allowed to cool to room temperature, and the mixture was extracted with water and 35 ethyl acetate. The extract was washed with saturated brine, 113 dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1->3:1) to give the title compound as colorless crystals (yield 72 mg, 5 68%). 1 H-NMR (CDCl 3 )S: 2.44 (3H, s), 6.75-6.77 (1H, m), 7.23-7.36 (4H, m), 7.50-7.51 (1H, m), 8.75 (1H, br), 9.85 (1H, s). Reference Example 114 4-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde 10 To a solution (15 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3 carbaldehyde (1.0 g) in N,N-dimethylformamide was added N chlorosuccinimide (0.71 g) at 00C, and the mixture was stirred at 600C for 2 hr. The mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl 15 acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyi acetate=8:1->3:1) to give the title compound as a yellow powder (yield 0.55 g, 20 46%). H-NMR (CDCl 3 )S: 7.15-7.40 (3H, m), 7.52 (1H, d, J=3.6 Hz), 7.97-8.03 (1H, m), 9.24 (1H, br), 9.96 (1H, s). Reference Example 115 4-fluoro-5-(2-fluorophenyl)-lH-pyrrole-3-carbaldehyde 25 To a solution (60 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3 carbaldehyde (3.1 g) in tetrahydrofuran was added 2,6 dichloro-N-fluoropyridinium triflate (5.6 g) at OOC, and the mixture was stirred at the same temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution was added 30 to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel 35 column chromatography (eluent: hexane-ethyl acetate=2:1) to 114 give the title compound as white crystals (yield 0.43 g, 13%). H-NMR (CDC1 3 )6; 7.11-7.30 (4H, m), 7.80-7.87 (1H, m), 9.14 (1H, brs), 9.88 (1H, s). Reference Example 116 5 4-fluoro-5-(2-methylphenyl)-1H-pyrrole-3-carbaldehyde Sodium hydride (0.40 g) was washed twice with hexane and suspended in tetrahydrofuran (10 mL). A solution of 3-fluoro 2-(2-methylphenyl)-1H-pyrrole (0.86 g) in tetrahydrofuran (3 mL) was added at OOC, and the mixture was stirred at the same 10 temperature for 30 min. A solution (2 mL) of triisopropylsilyl trifluoroacetate (2.7 mL) in tetrahydrofuran was added at 0CC, and the mixture was stirred at the same temperature for 15 min. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was 15 washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL) and acetonitrile (2 mL), (chloromethylene)dimethylammonium 20 chloride (1.6 g) was added, and the mixture was heated under reflux for 2 hr, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL), 1 mol/L aqueous sodium hydroxide solution (20 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction 25 mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography 30 (eluent: hexane-ethyl acetate=2:1) to give the title compound as a yellow oil (yield 0.48 g, 48%). H-NMR (CDCl 3 )S: 2.38 (3H, s), 7.23-7.32 (5H, m), 8.38 (1H, brs), 9.87 (1H, s). Reference Example 117 35 5-nitro-3-(trifluoromethyl)pyridin-2-ol 115 2-Hydroxy-3-(trifluoromethyl)pyridine (3.0 g) was added to conc. sulfuric acid (18 mL) under ice-cooling, and the mixture was stirred at the same temperature for 5 min. Fuming nitric acid (90-95%, 7 mL) was added dropwise Qver 5 min, and 5 the mixture was allowed to return to room temperature over 2 hr, heated to 500C and stirred for 3 hr. After cooling to room temperature, the reaction mixture was poured into ice (200 g), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous 10 magnesium sulfate, and concentrated under reduced pressure. The precipitate was washed with diisopropyl ether to give the title compound as a solid (yield 2.7 g, 69%). 1 H-NMR (CDCl 3 )8: 8.65-8.67 (1H, m), 8.80-8.81 (1H, m), 1H not detected. 15 Reference Example 118 2-chloro-5-nitro-3-(trifluoromethyl)pyridine A mixture of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.65 g), phosphorus pentachloride (3.17 g) and phosphorus oxychloride (1.5 mL) was stirred at 900C for 3 hr. After 20 cooling to room temperature, the reaction mixture was poured into ice, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column 25 chromatography (eluent: hexane-ethyl acetate=19:1-+3:1) to give the title compound as a yellow oil (yield 2.21 g, 77%). H-NMR (CDCl 3 ) 6: 8.79-8.81 (IH, m) , 9.40-9.41 (1H, m) Reference Example 119 6-chloro-5-(trifluoromethyl)pyridine-3-amine 30 Reduced iron (1.3 g) and ammonium chloride (2.1 g) were added to water (40 mL), and the mixture was stirred at room temperature for 5 min. A solution of 2-chloro-5-nitro-3 (trifluoromethyl)pyridine (1.8 g) in methanol (40 mL) was added, and the mixture was stirred at room temperature for 1 35 hr. Reduced iron (2.3 g) was added, and the mixture was 116 further stirred at the same temperature for 3 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine, 5 dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-+1:1) to give the title compound as a solid (yield 1.0 g, 65%). H-NMR (CDCl 3 )6: 7.29 (1H, m), 7.99 (1H, m), 2H not detected. 10 Reference Example 120 6-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride Under ice-cooling, thionyl chloride (4 mL) was added dropwise over 20 min to water (27 mL). The mixture was stirred at room temperature for 12 hr to give a sulfur dioxide 15 containing solution. Separately, 6-chloro-5 (trifluoromethyl)pyridine-3-amine (1.14 g) was added to concentrated hydrochloric acid (9 mL) with stirring under ice cooling, and concentrated hydrochloric acid (9 mL) was further added. A solution of sodium nitrite (0.44 g) in water (6 mL) 20 was added dropwise over 10 min. The reaction mixture was gradually added at SoC to the above-mentioned sulfur dioxide containing solution added with cuprous chloride (15 mg). Under ice-cooling, the mixture was further stirred for 30 min, and the precipitate was collected by filtration and washed with 25 water. The obtained precipitate was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1->9:1) to give the title compound as an orange solid (yield 437 mg, 27%). 'H-NMR (CDCl 3 ) 5: 8.58 (1H, m) , 9.18 (1H, m) . 30 Reference Example 121 6-chloro-2-methylpyridine-3-sulfonyl chloride Under ice-cooling, thionyl chloride (4 mL) was added dropwise to water (24 mL) over 20 min. The mixture was stirred at room temperature for 12 hr to give a sulfur dioxide 35 containing solution. Separately, to the concentrated 117 hydrochloric acid (6 mL) was added 5-amino-2-chloro-6 methylpyridine (1.0 g) with stirring under ice-cooling, and a solution of sodium nitrite (0.5 g) in water (2 mL) was added dropwise over 10 min. The reaction mixture was gradually added 5 at SOC to the above-mentioned sulfur dioxide-containing solution added with cuprous chloride (10 mg). Under ice cooling, the mixture was further stirred for 30 min, and the precipitate was collected by filtration, and washed with water to give the title compound as a pale-yellow solid (yield 1.1 1o g, 67%). 'H-NNR (CDCl 3 )S: 2.99 (3H, s), 7.41 (1H, dd, J=8.7, 0.9 Hz), 8.26 (1H, d, J=8.4 Hz) Reference Example 122 ethyl 1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3 15 carboxylate By a similar reaction as in Reference Example 40 and using 5-bromo-6-chloropyridine-3-sulfonyl chloride (3.49 g), the title compound was obtained as a yellow solid (yield 1.63 g, 38%). 20 'H-NMR (CDCl 3 )6: 1.35-1.39 (3H, m), 4.29-4.37 (2H, m), 6.60 (1H, s), 7.18-7.20 (2H, m), 7.35-7.51 (4H, m), 8.06 (1H, s), 8.45 (1H, s), 8.78 (1H, s). Reference Example 123 ethyl 5-phenyl-1-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl} 25 1H-pyrrole-3-carboxylate By a similar reaction as in Reference Example 40 and using 6-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride (413 mg), the title compound was obtained as a colorless solid (yield 191 mg, 35%). 30 1 H-NMR (CDCl 3 )6: 1.37 (3H, t, J=7.2 Hz), 4.33 (2H, dd, J=14.4, 7.2 Hz), 6.61 (1H, s), 7.16-7.18 (2H, m), 7.33-7.45 (3H, m), 7.65 (1H, s), 8.09 (1H, s), 8.75 (1H, s), 8.98 (1H, s). Reference Example 124 ethyl 1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole 35 3-carboxylate 118 By a similar reaction as in Reference Example 40 and using 6-chloro-2-methylpyridine-3-sulfonyl chloride (543 mg), the title compound was obtained as a red oil (yield 135 mg, 18%). 5 lH-NMR (CDCl 3 )6: 1.35-1.40 (3H, m), 2.47 (3H, s), 4.33 (2H, dd, J=14.1, 6.9 Hz), 6.59 (1H, d, J=1.8 Hz), 6.82-7.49 (7H, m), 8.21 (1H, d, J=2.1 Hz), 8.51 (1H, dd, J=4.8, 1.8 Hz). Reference Example 125 methyl 4-fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-1H-pyrrole 10 3-carboxylate By a similar reaction as in Reference Example 36 and using methyl 4-fluoro-5-phenyl-lH-pyrrole-3-carboxylate (172 mg), the title compound was obtained as a colorless solid (yield 206 mg, 73%). More specifically, to a solution of 125 methyl 4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (172 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 94 mg), and the mixture was stirred for 15 min. 15-Crown-S (0.48 mL) was added, and the mixture was further stirred for 15 min. Pyridine-3-sulfonyl chloride hydrochloride (219 mg) 20 was added and the mixture was stirred for 30 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel 25 column chromatography (eluent: hexane-ethyl acetate=19:1-+1:1) to give the title compound as a colorless solid (yield 206 mg, 73%). 1 H-NMR (CDCl 3 )S: 3.89 (3H, s), 7.17-7.20 (2H, m), 7.26-7.55 (5H, m), 7.95 (1H, d, J=4.8 Hz), 8.50-8.51 (1H, m), 8.76-8.78 30 (1H, m). Reference Example 126 1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-lH-pyrrole-3 carbaldehyde By a similar reaction as in Reference Example 62 and 35 .using ethyl 1-[(5-bromopyridin-3-yl)sulfonyll-5-phenyl-1H 119 pyrrole-3-carboxylate (1.63 g), the title compound was obtained as a pale-yellow solid (yield 1.18 g, 80%). 1 H-NMR (CDCl 3 )S: 6.63 (1H, s), 7.17-7.20 (2H, m), 7.36-7.39 (2H, m), 7.50-7.52 (2H, m), 8.10 (1H, s), 8.46 (1H, s), 8.79 5 8.80 (1H, m), 9.91 (1H, s). Reference Example 127 5-phenyl-l-{[5-(trifluoromethyl)pyridin-3-ylsulfonyl}-1H pyrrole-3-carbaldehyde By a similar reaction as in Reference Example 62 and 1o using ethyl 5-phenyl-1-{[(5-trifluoromethyl)pyridin-3 yl]sulfonyl}-1H-pyrrole-3-carboxylate (190 mg), the title compound was obtained as a colorless solid (yield 138 mg, 83%). 'H-NMR (CDCl 3 )S: 6.64 (1H, d, J=1.5 Hz), 7.15-7.18 (2H, m), 15 7.33-7.38 (2H, m), 7.44-7.47 (1H, m), 7.63-7.64 (1H, m), 8.14 (1H, d, J=1.5 Hz), 8.76 (1H, d, J=2.1 Hz), 9.00 (1H, d, J=1.5 Hz), 9.92 (1H, s). Reference Example 128 1-[(2-methylpyridin-3-yl)sulfonyll-5-phenyl-1H-pyrrole-3 20 carbaldehyde By a similar reaction as in Reference Example 62 and using ethyl 1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H pyrrole-3-carboxylate (364 mg), the title compound was obtained as an orange solid (yield 182 mg, 57%). 25 H-NMR (CDCl 3 )S: 2.47 (3H, s), 6.62 (1H, d, J=1.8 Hz), 6.83 6.90 (1H, m), 7.02-7.04 (2H, m), 7.16-7.31 (3H, m), 7.39-7.42 (1H, m), 8.24 (1H, s), 8.52-8.54 (1H, m), 9.93 (1H, s). Reference Example 129 4-fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 3o carbaldehyde Under a nitrogen atmosphere, a solution of methyl 4 fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carboxylate (200 mg) in tetrahydrofuran (10 mL) was cooled to -780C, and a 1.5 mol/L solution (1.85 mL) of diisobutylaluminum 35 hydride in toluene was added with stirring. After stirring at 120 the same temperature for 15 min, the mixture was raised to 0oC over 1.5 hr. Water (20 mL) was added, and the mixture was stirred at the same temperature for 5 min. After stirring, ethyl acetate (20 mL) was added, and the mixture was stirred 5 for 15 min, and then stirred at room temperature for 20 min. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and-concentrated under 10 reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), manganese dioxide (75% chemically treated product, 1.0 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The 15 filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-+1:2) to give the title compound as a colorless solid (yield 123 mg, 67%). 1 H-NMR (CDCl 3 )S. 7.17-7.20 (2H, m), 7.26-7.57 (5H, m), 7.96 20 (1H, d, J=4.8 Hz), 8.50-8.51 (1H, m), 8.76-8.80 (1H, m), 9.92 (1H, s). Reference Example 130 5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carbaldehyde 25 To a solution of 5-(2,6-difluorophenyl)-1H-pyrrole-3 carbaldehyde (420 mg) in tetrahydrofuran (42 mL) was added sodium hydride (60% in oil, 244 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (1.34 g) was added dropwise and the mixture was stirred for 30 min. 3 30 Pyridylsulfonyl chloride hydrochloride (565 mg) was added, and the mixture was further stirred for 1 hr. The reaction mixture was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium 35 sulfate, and concentrated under reduced pressure. The residue 121 was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3-*1:1), and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 590 mg, 84%). 5 1 H-NMR (CDCl 3 )S: 6.76 (1H, d, J=1.9 Hz), 6.90-6.95 (2H, m), 7.40-7.52 (2H, m), 7.77-7.81 (1H, m), 8.18 (1H, d, J=1.9 Hz), 8.65-8.66 (1H, m), 8.85-8.87 (1H, m), 9.91 (1H, s). Reference Example 131 5-(4-cyclohexylphenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrole-3 10 carbaldehyde Sodium hydride (60% in oil, 68 mg) was added to a solution of 5-(4-cyclohexylphenyl)-1H-pyrrole-3-carbaldehyde (0.17 g) in tetrahydrofuran (12 mL) at room temperature. The mixture was stirred for 20 min, 3-pyridinesulfonyl chloride 15 (0.19 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 20 The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2-->2:1) to give the title compound as crystals (yield 0.26 g, 97%). 1 H-NMR (CDCl 3 )6: 1.21-1.53 (5H, m), 1.73-1.98 (5H, m), 2.50 2.60 (1H, m), 6.57 (1H, d, J=1.9 Hz), 7.03-7.09 (2H, m), 7.13 25 7.29 (3H, m), 7.48 (1H, ddd, J=8.3, 2.0, 1.9 Hz), 8.11 (1H, d, J=1.9 Hz), 8.49 (1H, d, J=2.3 Hz), 8.73 (1H, dd, J=4.8, 1.6 Hz), 9.89 (1H, s). Reference Example 132 1-[(6-chloropyridin-3-yl)sulfonyl]-5-(2-fluorophenyl)-1H 3o pyrrole-3-carbaldehyde By a similar reaction as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) and.6-chloropyridine-3-sulfonyl chloride (1.30 g), the title compound was obtained as a pale-red solid (yield 1.14 g, 66%). 35 More specifically, 5-(2-fluorophenyl)-1H-pyrrole-3 122 carbaldehyde (893 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 226 mg) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (1.1 mL) was added and the mixture was further stirred at the 5 same temperature for 15 min. 6-Chloropyridine-3-sulfonyl chloride (1.30 g) was added. The reaction mixture was stirred at room temperature for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous lo magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-+3:2) to give the title compound as a pale-red solid (yield 1.14 g, 66%). 'H-NMR (CDCl 3 )5: 6.71 (1H, d, J=9.0 Hz), 7.05 (1H, t, J=9.0 15 Hz), 7.19-7.23 (2H, m), 7.38 (1H, d, J=8.4 Hz), 7.45-7.53 (1H, m), 7.63-7.67 (1H, m), 8.11 (1H, d, J=1.8 Hz), 8.33 (1H, d, J=2.7 Hz), 9.91 (1H, s). Reference Example 133 5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H 20 pyrrole-3-carbaldehyde Under an argon atmosphere, a mixture of 1-[(6 chloropyridin-3-yl)sulfonyl]-5-(2-fluorophenyl)-1H-pyrrole-3 carbaldehyde (365 mg), methylboronic acid (90 mg), tetrakis(triphenylphosphine)palladium (116 mg), potassium 25 carbonate (691 mg) and 1,4-dioxane (25 mL) was stirred at 80CC for 3 days. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and so concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-+1:1) to give the title compound as a yellow solid (yield 134 mg, 39%). 'H-NMR (CDCl 3 )S: 2.64 (3H, s), 6.67 (1H, d, J=1.8 Hz), 7.04 35 (1H, t, J=8.4 Hz), 7.17-7.21 (3H, m), 7.45-7.50 (1H, m), 7.58 123 (1H, dd, J=8.7, 3.6 Hz), 8.12 (1H, d, J=l.8 Hz), 8.45 (1H, d, J=2.4 Hz), 9.89 (1H, s). Reference Example 134 5-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrole-3 5 carbaldehyde By a similar reaction as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (190 mg) and pyridine-2-sulfonyl chloride (231 mg), the title compound was obtained as a pale-red solid (yield 183 mg, 55%). 10 1 H-NMR (CDCl 3 )S: 6.67 (1H, d, J=1.8 Hz), 6.97 (1H, t, J=8.7 Hz), 7.07-7.10 (2H, m), 7.36-7.42 (1H, m), 7.52-7.55 (2H, m), 7.76-7.82 (1H, m), 8.23 (1H, d, J=1.5 Hz), 8.67 (1H, d, J=4.5 Hz), 9.92 (1H, s). Reference Example 135 15 5-(2-fluorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-iH pyrrole-3-carbaldehyde By a similar operation as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (189 mg) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (217 mg), the 20 title compound was obtained as yellow crystals (yield 217 mg, 65%). 1 H-NNR (CDCl 3 )6: 3.85 (3H, s), 6.67 (1H, d, J=1.8 Hz), 7.04 7.11 (1H, m), 7.17-7.22 (1H, m), 7.25-7.35 (3H, m), 7.43-7.50 (1H, m), 8.06 (1H, d, J=1.5 Hz), 9.86 (1H, s). 25 Reference Example 136 5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrole-3 carbaldehyde To a solution of 5-(2-methylphenyl)-1H-pyrrole-3 carbaldehyde (371 mg) in tetrahydrofuran (10 mL) were added 30 sodium hydride (60% in oil, 288 mg) and 15-crown-5 (1.32 g) at room temperature. After stirring for 5 min, a suspension of pyridine-3-sulfonyl chloride hydrochloride (642 mg) in N,N dimethylformamide (5 mL) was added at the same temperature. After stirring for 15 min, ice water was added, and the 35 mixture was extracted with ethyl acetate. The extract was 124 washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1-*3:1) to give the title compound as a 5 red oil (yield 521 mg, 80%). 'H-NMR (CDCl 3 )S: 1.82 (3H, s), 6.56 (1H, d, J=1.5 Hz), 6.87 6.90 (1H, m), 7.11-7.19 (2H, m), 7.30-7.39 (2H, m), 7.56-7.60 (1H, m), 8.15 (1H, d, J=1.5 Hz), 8.52-8.53 (1H, m), 8.80-8.82 (1H, m), 9.92 (1H, s) . 10 Reference Example 137 4-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrole-3-carbaldehyde A suspension of sodium hydride (60% in oil, 216 mg) in tetrahydrofuran (5 mL) was cooled to 0CC, a solution of 4 15 chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (335 mg) in tetrahydrofuran (5 mL), 15-crown-5 (991 mg), and pyridine 3-sulfonyl chloride hydrochloride (482 mg) were added at 100C or below. After stirring for 15 min, water was added, and the mixture was extracted with ethyl acetate. The extract was 20 washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1-2:1) to give the title compound as a yellow powder (yield 429 mg, 78%). 25 1 H-NMR (CDCl 3 )6: 7.02-7.08 (1H, m), 7.19-7.29 (2H, m), 7.37 7.41 (1H, m), 7.50-7.57 (1H, m), 7.68-7.72 (1H, m), 8.15 (1H, s), 8.54-8.55 (1H, m), 8.83-8.86 (1H, m), 9.97 (1H, s). Reference Example 138 4-fluoro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H 30 pyrrole-3-carbaldehyde Sodium hydride (60% in oil, 0.25 g) was washed twice with hexane and suspended in tetrahydrofuran (10 mL). A solution (5 mL).of 4-fluoro-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (0.43 g) in tetrahydrofuran was added at 0CC, and the mixture 35 was stirred at the same temperature for 30 min. 15-Crown-5 125 (1.3 mL) and 3-pyridinesulfonyl chloride hydrochloride (0.68 g) were added at 00C, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract 5 was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound 20 as pale-yellow crystals (yield 0.55 g, 76%). 1 H-NMR (CDCl 3 )S: 7.02-7.08 (1H, m), 7.20-7.31 (2H, m), 7.36 7.41 (1H, m), 7.48-7.55 (1H, m), 7.67-7.71 (1H, m), 8.00 (1H, d, J=5.1 Hz), 8.55-8.56 (1H, m), 8.83-8.85 (1H, m), 9.93 (1H, s). 15 Reference Example 139 4-fluoro-5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrole-3-carbaldehyde Sodium hydride (60% in oil, 0.11 g) was washed twice with hexane and suspended in tetrahydrofuran (10 mL). A solution (5 20 mL) of 4-fluoro-5-(2-methylphenyl)-1H-pyrrole-3-carbaldehyde (0.45 g) in tetrahydrofuran was added at 00C, and the mixture was stirred at the same temperature for 15 min. A solution (2 mL) of 15-crown-5 (0.56 mL) and 3-pyridinesulfonyl chloride (0.44 g) in tetrahydrofuran was added at OOC, and the mixture 25 was stirred at the same temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and 30 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as pale-yellow crystals (yield 0.59 g, 77%). 'H-NMR (CDCl 3 )S: 1.77 (3H, s), 7.02-7.04 (1H, m), 7.17-7.23 35 (2H, m), 7.29-7.34 (1H, m), 7.37-7.42 (1H, m), 7.54-7.58 (1H, 126 m), 8.00 (1H, d, J=4.5 Hz), 8.49-8.50 (1H, m), 8.81-8.83 (1H, m), 9.92 (1H, s). Reference Example 140 2-chloro-5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H 5 pyrrole-3-carbaldehyde To a solution of 5-(2,6-difluorophenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrole-3-carbaldehyde (250 mg) in tetrahydrofuran (10 mL) and N,N-dimethylformamide (10 mL) was added N-chlorosuccinimide (1.06 g) and the mixture was stirred 10 for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed.with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue 15 was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3->1:1) to give the title compound as a pale-yellow oil (yield 160 mg, 58%). 1 H-NMR (CDCl 3 )8: 6.74 (1H, s), 7.00-7.05 (2H, m), 7.42-7.56 (2H, m), 8.10-8.14 (1H, m), 8.91 (1H, dd, J=4.9, 1.5 Hz), 9.07 20 (1H, d, J=2.1 Hz), 9.92 (1H, s). Reference Example 141 2-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrole-3-carbaldehyde To a solution of 5-(2-fluorophenyl)-1-(pyridin-3 25 ylsulfonyl)-1H-pyrrole-3-carbaldehyde (331 mg) in N,N dimethylformamide (33 mL) was added N-chlorosuccinimide (268 mg) and the mixture was stirred at 600C for 1 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl 3o acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel colun chromatography (eluent: hexane-ethyl acetate=7:3-+1:1) to give the title compound as a colorless oil (yield 250 mg, 35 68%). 127 'H-NMR (CDCl3)6: 6.65 (1H, s), 7.13-7.35 (3H, m), 7.45-7.55 (2H, m), 8.09-8.13 (1H, m), 8.90-9.03 (2H, m), 9.92 (1H, s). Reference Example 142 tert-butyl ({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-3-yl 5 1H-pyrrol-3-yl}methyl)methylcarbamate 1-[(5-Bromopyridin-3-yl)sulfonyll-5-phenyl-1H-pyrrole-3 carbaldehyde (1.18 g) was dissolved in absolute tetrahydrofuran (15 mL), a 2 mol/L solution (4.6 mL) of methylamine in tetrahydrofuran was added, and the mixture was lo stirred at room temperature for 16 hr. The reaction mixture was added to a solution of sodium borohydride (341 mg) in methanol (6 mL), and the mixture was stirred at the same temperature for 5 min. di-tert-Butyl bicarbonate (3.87 g) was added, and water (15 mL) and sodium hydrogencarbonate (1.26 g) 15 were added 5 min later. The mixture was further stirred at room temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 20 The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-+1:1), and fractions showing Rf values of 0.63, 0.30 and 0.075 (eluent: hexane-ethyl acetate=3:1) by TLC analysis were collected and concentrated under reduced pressure. The residue was dissolved in 25 tetrahydrofuran (30 mL), manganese dioxide (75% chemically treated product, 3.0 g) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, 30 and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-1:1) to give the title compound as a colorless oil (yield 733 mg, 48%). 'H-NMR (CDCl 3 )S: 1-.47 (9H, s), 2.82 (3H, s), 4.23 (2H, m), 6.16 (1H, s), 7.21-7.56 (7H, m), 8.44 (1H, s), 8.76 (1H, s). 35 Reference Example 143 128 tert-butyl { [5- (2, 4-dimethylphenyl) -1- (pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl]methyl}methylcarbamate.. By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 5 3-yl]methyl}methylcarbamate (300 mg), (4-fluorophenyl)boronic acid (209 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 177 mg,.56%). H-NMR (CDCl 3 )8: 1.46 (9H, s), 1.89 (3H, s), 2.36 (3H, s), 2.83 10 (3H, s), 4.25 (2H, brs), 6.03-6.04 (1H, m), 6.76 (1H, d, J=8.1 Hz), 6.92-6.95 (1H, m), 7.00 (1H, brs), 7.26-7.33 (2H, m), 7.61-7.65 (1H, m), 8.56-8.57 (1H, m), 8.75-8.77 (1H, m). Reference Example 144 tert-butyl {[5-(2-formylphenyl)-1-(pyridin-3-ylsulfonyl)-1H 15 pyrrol-3-yl]methyl}methylcarbamate tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]methyl}methylcarbamate (430 mg) was dissolved in toluene (10 mL), and the mixture was sufficiently degassed. Dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (66 mg) 20 and tris(dibenzylideneacetone)dipalladium (0) (37 mg) were added at room temperature. The mixture was stirred for 30 min with degassing, and a 2 mol/L aqueous sodium carbonate solution (1.2 mL) and (2-formylphenyl)boronic acid (180 mg) were added. After further stirring at room temperature for 15 25 min, the mixture was heated to 1200C over 1 hr, and further stirred for 16 hr. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated 3o under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1-+1:1) to give the title compound as a yellow oil (yield 218 mg, 48%),. H-NMR (CDCl 3 )8: 1.47 (9H, s), 2.86 (3H, s), 4.27 (2H, brs), 35 6.23 (1H, brs), 7.09-7.11 (1H, m), 7.28-7.33 (1H, m), 7.43 129 (1H, d, J=1.2 Hz), 7.53-7.61 (3H, m), 7.96-7.99 (1H, m), 8.49 8.50 (1H, m), 8.75-8.77 (1H, m), 9.61-9.62 (1H, m). Reference Example 145 tert-butyl methyl{[5-[4-(methylsulfonyl)phenyll-1-(pyridin-3 5 ylsulfonyl)-1H-pyrrol-3-yllmethyl}carbamate A mixture of tert-butyl {[5-bromo-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), 4 (methanesulfonyl)phenylboronic acid (300 mg), tetrakis(triphenylphosphine)palladium (115 mg), sodium 10 carbonate (320 mg), 1,2-dimethoxyethane (10 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80C for 14 hr. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, 15 dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1->1:2) to give the title compound as an oil (yield 275 mg, 64%). 'H-NNR (CDCl 3 )6: 1.26 (9H, s), 2.79 (3H, s), 3.13 (3H, s), 4.22 20 (2H, s), 6.26 (1H, s), 7.26-7.37 (2H, m), 7.44-7.71 (3H, m), 7.93 (2H, d, J=8.3 Hz), 8.58 (1H, d, J=2.1 Hz), 8.76 (1H, dd, J=4.9, 1.5 Hz). Reference Example 146 tert-butyl ({5-[2-(hydroxymethyl)phenyl]-1-(pyridin-3 25 ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate tert-Butyl {[5-(2-formylphenyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl]methyl}methylcarbamate (218 mg) was dissolved in tetrahydrofuran (2 mL), and sodium borohydride (24 mg) and methanol (1 mL) were added at 00C. After stirring at the same 30 temperature for 30 min, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl 35 acetate=1:1-l: 3 ) to give the title compound as a colorless oil 130 (yield 132 mg, 60%). lH-NMR (CDCl 3 )8: 1.46 (9H, s), 2.10-2.15 (1H, m), 2.85 (3H, s), 4.25 (2H, brs), 4.30-4.38 (2H, m), 6.12 (1H, d, J=1.5 Hz), 6.69-6.72 (1H, m), 7.13-7.18 (1H, m), 7.30-7.35 (2H, m), 7.44 5 7.49 (1H, m), 7.59-7.62 (2H, m), 8.50 (1H, d, J=2.4 Hz), 8.76 8.78 (1H, m). Reference Example 147 5-mesityl-1H-pyrrole-3-carbaldehyde A mixture of 5-bromo-1H-pyrrole-3-carbaldehyde (0.87 g), 10 2,4,6-trimethylphenylboronic acid (3.28 g), cesium carbonate (13.0 g), tri-tert-butylphosphine (0.10 g), tris(dibenzylideneacetone)dipalladium (0) (0.23 g) and mesitylene (200 mL) was stirred with heating under reflux for 5 hr. Water was added to the reaction mixture, and the mixture 15 was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:1) to give the title compound as a brown amorphous 20 form (yield 0.30 g, 28%). IH-NMR (CDCl 3 )8: 2.11 (6H, s), 2.32 (3H, s), 6.51-6.52 (1H, m), 6.93 (2H, s), 7.47-7.49 (iH, m), 9.82 (1H, s), IH not detected. Reference Example 148 25 5-[2-(methylthio)phenyl-1H-pyrrole-3-carbaldehyde 5-Bromo-lH-pyrrole-3-carbaldehyde (174 mg), [2 (methylthio)phenyllboronic acid (202 mg) and sodium carbonate (254 mg) were suspended in a mixed solvent of 1,2 dimethoxyethane (5 mL) and water (2 mL), and the mixture was 30 sufficiently degassed under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium (58 mg) was added, and the mixture was further degassed and stirred at 1050C for 16 hr.. The reaction mixture was allowed to cool to room temperature, water was added and the mixture was extracted 35 with ethyl acetate. The extract was washed with saturated 131 brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1-+4:1) to give the title compound as pale-yellow crystals (yield 150 5 mg, 69%). 'H-NMR (CDCl 3 )S: 2.38 (3H, s), 6.94-6.95 (1H, m), 7.21-7.31 (2H, m), 7.39-7.42 (1H, m), 7.48-7.53 (2H, m), 9.85 (iH, s), 9.95 (1H, br). Reference Example 149 10 5- (2-bromophenyl)-1H-pyrrole-3-carbaldehyde By a similar operation as in Reference Example 148 and using 5-bromo-lH-pyrrole-3-carbaldehyde (870 mg), (2 bromophenyl)boronic acid (1.20 g), sodium carbonate (1.27 g) and tetrakis(triphenylphosphine)palladium (289 mg), the title a5 compound was obtained as colorless crystals (yield 396 mg, 32%). 1 H-NMER (CDCl 3 )8: 6.94-6.95 (1H, m), 7.16-7.22 (1H, m), 7.34 7.39 (1H, m), 7.49-7.54 (2H, m), 7.63-7.66 (1H, m), 9.28 (1H, br), 9.85 (1H, s). 20 Reference Example 150 5-[2-(methylsulfinyl)phenyl]-iH-pyrrole-3-carbaldehyde To a solution of 5-[2-(methylthio)phenyl]-1H-pyrrole-3 carbaldehyde (200 mg) in ethyl acetate (10 mL) was added 3 chloroperbenzoic acid (238 mg) under ice-cooling. After 25 stirring at room temperature for 1 hr, a saturated sodium thiosulfate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The 3o residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound as a pale pink powder (yield 160 mg, 75%). 'H-NMR (CDCl 3 )6: 2.64 (3H, s), 7.04-7.06 (iH, m), 7.35-7.41 (iH, m), 7.57-7.64 (2H, m), 7.72-7.82 (2H, m), 9.86 (1H, s), 35 12.35 (1H, br). 132 Reference Example 151 5-[2-(methylsulfonyl)phenyl)-lH-pyrrole-3-carbaldehyde To a solution of 5-[2-(methylthio)phenyl]-1H-pyrrole-3 carbaldehyde (100 mg) in ethyl acetate (5 mL) was added 3 5 chloroperbenzoic acid (318 mg) under ice-cooling. After stirring at room temperature for 3 hr, a saturated sodium thiosulfate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous 10 sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1->1:3) to give the title compound as pale-yellow crystals (yield 88.9 mg, 78%). 'H-NMR (CDC1 3 )6: 2.77 (3H, s), 6.94-6.96 (1H, m), 7.54-7.60 15 (2H, m), 7.67-7.73 (2H, m), 8.20-8.24 (1H, m), 9.88 (1H, s), 10.60 (1H, s). Reference Example 152 5-(2-fluorophenyl)-4-iodo-lH-pyrrole-3-carbaldehyde 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (2.0 g) was 20 dissolved in N,N-dimethylformamide (60 mL), N-iodosuccinimide (2.38 g) was added and the mixture was stirred at for 12 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate 25 solution, a 3% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7: 3 -l:1) to give the title compound as a pale-brown 30 powder (yield 450 mg, 14%). 1 H-NMR (CDCl 3 )6: 7.16-7.30 (2H, m), 7.37-7.44 (1H, m), 7.63 (1H, d, J=3.4 Hz), 7.81-7.86 (1H, m), 9.24 (1H, br), 9.81 (1H, s) . Reference Example 153 35 5-mesityl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde 133 To a solution of 5-mesityl-1H-pyrrole-3-carbaldehyde (0.36 g) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 0.14 g) under ice-cooling, and the mixture was stirred at room temperature for 0.5 hr. A solution of 15 5 crown-5 (0.75 g) in tetrahydrofuran (3 mL) was added and, after stirring for 5 min, pyridin-3-ylsulfonyl chloride (0.45 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 0.5 hr, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction lo mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1-+2:1) to give the title 15 compound as a pale-brown amorphous form (yield 0.38 g, 62%). 'H-NMR (CDCl 3 )6: 1.63 (6H, s), 2.35 (3H, s), 6.48 (1H, d, J=1.5 Hz), 6.83 (2H, s), 7.26-7.35- (1H, m), 7.60-7.64 (1H, m), 8.17 (1H, dd, J=1.5, 0.9 Hz), 8.56 (1H, d, J=2.1 Hz), 8.83 (1H, dd, ,=4.5, 1.5 Hz), 9.90 (1H, s). 20 Reference Example 154 5-[2-(methylthio)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrole 3-carbaldehyde To a suspension of sodium hydride (60% in oil, 40 mg) in tetrahydrofuran (3 mL) were added a solution of 5-[2 25 (methylthio)phenyl]-1H-pyrrole-3-carbaldehyde (150 mg) in tetrahydrofuran (5 mL), 15-crown-5 (182 mg) and pyridin-3 ylsulfonyl chloride (135 mg) under ice-cooling. After stirring at room temperature for 2 hr, water was added and the mixture was extracted with ethyl acetate. The extract was washed with 30 saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1-*2:1) to give the title compound as colorless crystals (yield 170 mg, 69%). 35 1 H-NMR (CDCl 3 )S: 2.05 (3H, s), 6.68 (1H, d, J=2.1 Hz), 6.97 134 6.99 (1H, m), 7.17-7.31 (3H, m), 7.40-7.45 (1H, m), 7.65-7.70 (1H, m), 8.16 (1H, d, J=2.1 Hz), 8.45-8.46 (1H, m), 8.75-8.77 (1H, m), 9.90 (1H, s). Reference Example 155 5 5-(2-bromophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carbaldehyde By a similar operation as in Reference Example 154 and using sodium hydride (60% in oil, 91.0 mg), 5-(2-bromophenyl) 1H-pyrrole-3-carbaldehyde (396 mg), 15-crown-5 (418 mg) and 10 pyridin-3-ylsulfonyl chloride (309 mg), the title compound was obtained as a pale-yellow solid (yield 560 mg, 91%). 'H-NMR (CDCl 3 )S: 6.66 (1H, d, J=1.5 Hz), 7.31-7.40 (4H, m), 7.48-7.52 (1H, m), 7.66-7.71 (1H, m), 8.15 (1H, d, J=1.8 Hz), 8.55 (1H, d, J=2.7 Hz), 8.82-8.84 (1H, m), 9.92 (1H, s). 15 Reference Example 156 5-[2-(methylsulfonyl)phenyll-1-(pyridin-3-ylsulfonyl)-1H pyrrole-3-carbaldehyde By a similar operation as in Reference Example 154 and using sodium hydride (60% in oil, 40 mg), 5-[2 20 (methylsulfonyl)phenyll-1H-pyrrole-3-carbaldehyde (88.9 mg), 15-crown-5 (94.4 mg) and pyridin-3-ylsulfonyl chloride (69.7 mg), the title compound was obtained as a colorless amorphous form (yield 72.0 mg, 52%). H-NMR (CDCl3)S: 2.87 (3H, s), 6.67 (1H, d, J=1.8 Hz), 7.37 25 7.48 (2H, m), 7.72-7.76 (3H, m), 8.02-8.05 (1H, m), 8.14 (1H, d, J=1.8 Hz), 8.50 (1H, d, J=2.7 Hz), 8.81-8.83 (1H, m), 9.89 (1H, s). Reference Example 157 2-[4-formyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-2 30 yllbenzonitrile A suspension of 5-(2-bromophenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrole-3-carbaldehyde (102 mg), zinc cyanide (61..0 mg) and tetrakis(triphenylphosphine)palladium (60.0 mg) in N,N-dimethylformamide (2 mL) was heated (100 W, 4 min 30 35 sec) using a microwave focused chemical synthesis reactor 135 manufactured by CEM, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue 5 was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1-*2:1) to give the title compound as a pale-yellow oil (yield 97.4 mg, 63%). 1 H-NMR (CDCl 3 )S: 6.79 (1H, d, J=1.8 Hz), 7.41-7.51 (2H, m), 7.58-7..78 (4H, m), 8.17 (1H, d, J=1.5 Hz), 8.45 (1H, d, J=2.7 10 Hz), 8.84-8.86 (1H, m), 9.91 (1H, s). Reference Example 158 5-(2-fluorophenyl)-4-iodo-1-(pyridin-3-ylsulfonyl)-1H-pyrrole 3-carbaldehyde To a solution (42 mL) of 5-(2-fluorophenyl)-4-iodo-lH 15 pyrrole-3-carbaldehyde (400 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 102 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (560 mg) was added dropwise and the mixture was stirred for 30 min. Pyridin-3-ylsulfonyl chloride (340 mg) was added, and the 20 mixture was further stirred for 1 hr. The reaction mixture was diluted with saturated brine and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified 25 by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2-+1:1) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 540 mg, 93%). 1 H-NMR (CDCl 3 )6: 7.01-7.07 (1H, m), 7.12-7.17 (1H, m), 7.23 3o 7.28 (1H, m), 7.37-7.41 (1H, m), 7.50-7.58 (1H, m), 7.69-7.73 (1H, m), 8.21 (1H, s), 8.54-8.54 (1H, m), 8.85 (1H, dd, J=4.9, 1.5 Hz), 9.85 (1H, s). Reference Example 159 5-(2,6-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 35 carbaldehyde 136 A mixture of 5-bromo-1H-pyrrole-3-carbaldehyde (0.87 g), 2,6-dimethylphenylboronic acid (4.50 g), cesium carbonate (13.0 g), tri-tert-butylphosphine (0.10 g), tris(dibenzylideneacetone)dipalladium (0) (0.23 g) and 5 mesitylene (200 mL) was stirred with heating under reflux for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified 1o by silica gel column chromatography (eluent: hexane-ethyl acetate=3:1) to give a brown oil (0.48 g) . To a solution of the oil in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 0.19 g) under-ice-cooling, and the mixture was stirred at room temperature for 0.5 hr. A solution of 15 15 crown-5 (1.06 g) in tetrahydrofuran (3 mL) was added, and the mixture was stirred for 5 min. Pyridin-3-ylsulfonyl chloride (0.64 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 0.5 hr, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture 20 was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a pale-brown oil 25 (yield 0.42 g, 25%). 1 H-NMR (CDCl 3 )S: 1.66 (6H, s), 6.52 (1H, d, J=2.1 Hz), 6.70 (2H, d, J=7.5 Hz), 7.25-7.34 (2H, m), 7.56-7.60 (1H, m), 8.19 (1H, d, J=1.5 Hz), 8.53 (1H, d, J=1.8 Hz), 8.81-8.83 (1H, m), 9.91 (1H, s). 30 Reference Example 160 2-bromo-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH pyrrole-3-carbaldehyde . 5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carbaldehyde (330 mg) was dissolved in N,N-dimethylformamide 35 (30 mL), N-bromosuccinimide (356 mg) was added and the mixture 137 was stirred at 800C for 2 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over 5 anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 270 mg, 66%). 10 'H-NMR (CDC1 3 )5: 6.70 (1H, s), 7.12-7.26 (2H, m), 7.29-7.35 (1H, m), 7.44-7.52 (2H, m), 8.07-8.11 (1H, m), 8.89 (1H, dd, J=4.9, 1.5 Hz), 9.01-9.02 (1H, m), 9.86 (1H, s). Reference Example 161 2-(2-fluorophenyl)-4-formyl-1-(pyridin-3-ylsulfonyl)-1H 15 pyrrole-3-carbonitrile 5-(2-Fluorophenyl)-4-iodo-l-(pyridin-3-ylsulfonyl)-1H pyrrole-3-carbaldehyde (489 mg), copper (I) cyanide (480 mg), tris(dibenzylideneacetone)dipalladium (0) (49 mg) and 1,1' bis(diphenylphosphino)ferrocene (89 mg) were mixed in 1,4 20 dioxane (20 mL), and the mixture was heated under reflux for 3 hr. The reaction mixture was allowed to cool, diluted with ethyl acetate, and filtered. The obtained filtrate was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and 25 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:3->3: 7 ) to give the title compound as a colorless oil (yield 380 mg, about 100%). 1 H-NMR (CDCl 3 )6: 7.06-7.12 (1H, m), 7.24-7.32 (2H, m), 7.40 3o 7.45 (1H, m), 7.55-7.63 (1H, m), 7.70-7.74 (1H, m), 8.19 (1H, s), 8.57 (1H, d, J=1.9 Hz), 8.88 (1H, dd, J=4.8, 1.6 Hz), 9.97 (1H, s). Reference Example 162 5-(2-fluorophenyl)-3-formyl-1-(pyridin-3-ylsulfonyl)-1H 3.5 pyrrole-2-carbonitrile 138 2-Bromo-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH pyrrole-3-carbaldehyde (340 mg), copper (I) cyanide (400 mg), tris(dibenzylideneacetone)dipalladium (0) (40 mg), 1,1' bis(diphenylphosphino)ferrocene (70 mg) were mixed in 1,4 5 dioxane (30 mL), and the mixture was heated under reflux for 24 hr. The reaction mixture was allowed to cool, diluted with ethyl acetate, and filtered. The obtained filtrate was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and 10 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 169 mg, 57%). 1 H-NMR (CDCl 3 )5: 6.72 (1H, s), 7.12-7.18 (1H, m), 7.24-7.28 15 (2H, m), 7.50-7.60 (2H, m), 8.10-8.14 (1H, m), 8.82 (1H, d, J=2.4 Hz), 8.92 (1H, dd, J=4.9, 1.5 Hz), 10.09 (1H, s). Reference Example 163 tert-butyl ({5-bromo-1-[(6-methoxypyridin-3-yl)sulfonyl]-1H pyrrol-3-yl}methyl)methylcarbamate 20 Sodium hydride (60% in oil, 433 mg) was washed twice with hexane, and suspended in tetrahydrofuran (20 mL). A solution of tert-butyl [(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (2.66 g) in tetrahydrofuran (10 mL) was added to the suspension at 00C, and a solution of 15-crown-5 (2.20 mL) and 25 6-methoxypyridin-3-ylsulfonyl chloride (2.29 g) in tetrahydrofuran (5 mL) was added at the same temperature. After stirring at room temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous 30 sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1) to give the title compound as a brown oil (yield 4.02 g, 95%). 35 1 H-NMR (CDCl 3 )6: 1.47 (9H, s), 2.79 (3H, brs), 4.01 (3H, s), 139 4.17 (2H, brs), 6.25 (1H, brs), 6.82 (1H, d, J=9.0 Hz), 7.32 (1H, brs), 7.94-7.98 (1H, m), 8.77-8.78 (1H, m). Reference Example 164 tert-butyl {[5-(4-cyanophenyl)-1-(pyridin-3-ylsulfonyl)-1H 5 pyrrol-3-yl methyl}methylcarbamate By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]methyl}methylcarbamate (430 mg), (4-cyanophenyl)boronic acid (176 mg), sodium carbonate (254 mg) and 10 tetrakis(triphenylphosphine)palladium (57.8 mg), the title compound was obtained as a pale-yellow oil (yield 382 mg, 84%). 1 H-NMR (CDC1 3 )5: 1.46 (9H, s), 2.79 (3H, s), 4.21 (2H, brs), 6.23 (1H, brs), 7.28-7.34 (2H, m), 7.39-7.43 (2H, m), 7.59 15 7.66 (3H, m), 8.55 (1H, d, J=2.1 Hz), 8.74-8.76 (1H, m). Reference Example 165 tert-butyl {[5-(5-cyano-2-fluorophenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yllmethyl}methylcarbamate By a similar operation as in Reference Example 79 and 20 using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]methyl}methylcarbamate (430 mg), (5-cyano-2 fluorophenyl)boronic acid (198 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (57.8 mg), the title compound was obtained as a pale-yellow oil (yield 28.9 mg, 25 6%). 1 H-NMR (CDCl 3 )5: 1.46 (9H, s), 2.82 (3H, s), 4.24 (2H, brs), 6.28 (1H, brs), 7.21 (1H, t, J=8.7 Hz), 7.35-7.42 (2H, m), 7.49-7.52 (1H, m), 7.69-7.73 (2H, m), 8.66 (1H, d, J=2.4 Hz), 8.81-8.83 (1H, m). 30 Reference Example 166 tert-butyl {[5-(2-fluoro-5-methoxyphenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]methyl methylcarbamate , tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-iH-pyrrol 3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-5 35 methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate 140 (253 mg) and tetrakis(triphenylphosphine)palladium (174 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 90*C for 1 hr. The reaction mixture was allowed 5 to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column 1o chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 475 mg, about 100%). 1 H-NMR (CDCl 3 )S: 1.47 (9H, s), 2.83 (3H, s), 3.78 (3H, s), 4.24 (2H, s), 6.22 (1H, d, J=1.1 Hz), 6.69-6.71 (1H, m), 6.90-6.98 (2H, m), 7.72-7.36 (2H, m), 7.69-7.73 (1H, m), 8.65 (1H, d, 15 J=2.3 Hz), 8.77 (1H, dd, J=4.9, 1.5 Hz). Reference Example 167 tert-butyl {[5-(2-fluoro-3-formylphenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yllmethyl}methylcarbamate By a similar operation as in Reference Example 79 and 20 using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]methyl}methylcarbamate (430 mg), (2-fluoro-3 formylphenyl)boronic acid (252 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (173 mg), the title compound was obtained as a pale-yellow oil (yield 250 mg, 25 53%). 'H-NMR (CDCl 3 )S: 1.47 (9H, s), 2.83 (3H, s), 4.25 (2H, brs), 6.28 (1H, brs), 7.26-7.46 (4H, m), 7.68-7.72 (1H, m), 7.92 7.97 (1H, m), 8.61 (1Hj d, J=2.1 Hz), 8.77-8.79 (1H, m), 10.30 (1H, s). 30 Reference Example 168 tert-butyl {[5-(3-acetyl-2-fluorophenyl)-1-(pyridin-3 ylsulfonyl)-lH-pyrrol-3-ylmethyl}methylcarbamate . By a similar operation as in Reference Example 79 and using tert-butyl ([5-bromo-1-(pyridin-3-ylsulfonyl)-lH-pyrrol 35 3-yl]methyl}methylcarbamate (430 mg), (3-acetyl-2 141 fluorophenyl)boronic acid (273 mg), sodium carbonate (254 mg), and tetrakis(triphenylphosphine)palladium (173 mg), the title compound was obtained as a pale-yellow oil (yield 443 mg, 91%). 5 1 H-NMR (CDCl 3 )S: 1.47 (9H, s), 2.59 (3H, d, J=5.4 Hz), 2.83 (3H, s), 4.25 (2H, brs), 6.24 (1H, brs), 7.19-7.36 (4H, m), 7.66-7.70 (1H, m), 7.90-7.96 (1H, m), 8.60 (1H, d, J=2.4 Hz), 8.76-8.78 (iH, m). Reference Example 169 10 tert-butyl {[5-(2-fluoropyridin-3-yl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl methyl}methylcarbamate A suspension of tert-butyl {[5-bromo-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yllmethyl}methylcarbamate (430 mg), (2-fluoropyridin-3-yl)boronic acid (221 mg), sodium carbonate 15 (254 mg) and tetrakis(triphenylphosphine)palladium (173 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was stirred at 105 0 C for 1 hr. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was 20 washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1-1:1) to give the title compound as a pale-yellow oil (yield 310 mg, 69%). 25 1 H-NMR (CDCl 3 )5: 1.46 (9H, s), 2.82 (3H, s), 4.23 (2H, brs), 6.29 (1H, brs), 7.23-7.27 (1H, m), 7.34-7.39 (2H, m), 7.66 7.73 (2H, m), 8.25-8.27 (1H, m), 8.66 (1H, d, J=2.4 Hz), 8.78 8.80 (1H, m). Reference Example 170 30 tert-butyl {[5-(3-fluoropyridin-4-yl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl methyl}methylcarbamate tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]methyl}methylcarbamate (215 mg), (3-fluoropyridin-4 yl)boronic acid hydrate (120 mg), sodium hydrogencarbonate 35 (126 mg) and tetrakis(triphenylphosphine)palladium (87 mg) 142 were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 800C for 3 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution 5 was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the lo title compound as a pale-yellow oil (yield 60 mg, 27%). 'H-NMR (CDCl 3 )S: 1.47 (9H, s), 2.61 (3H, s), 4.24 (2H, s), 6.35 (1H, s), 7.22-7.26 (1H, m), 7.35-7.40 (2H, m), 7.71-7.75 (1H, m), 8.47 (iH, d, J=4.8 Hz), 8.50 (1H, d, J=1.3 Hz), 8.70 (1H, d, J=2.1 Hz), 8.81 (1H, dd, J=4.8, 1.6 Hz). 15 Reference Example 171 tert-butyl {[5-(2-chloropyridin-3-yl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-iH-pyrrol 3-yl]methyl}methylcarbamate (431 mg), (2-chloropyridin-3 20 yl)boronic acid (237 mg), sodium hydrogencarbonate (126 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 1000C for 3 hr. The reaction mixture was allowed 25 to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column 30 chromatography (eluent: hexane-ethyl acetate=1:1-+1:4) to give the title compound as a colorless oil (yield 280 mg, 60%). 1 H-NNR (CDCl 3 )5: 1.47 (9H, s), 2.84 (3H, s), 4.27 (2H, s), 6.30 (1H, s), 7.30-7.39 (3H, m), 7.65-7.73 (2H, m), 8.43-8.45 (1H, m), 8.67 (1H, d, J=2.3 Hz), 8.80 (1H, dd, J=4.9, 1.5 Hz). 35 Reference Example 172 143 tert-butyl {[5-(6-chloropyridin-3-yl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl methyl}methylcarbamate Reference Example 173 tert-butyl {[5-(6'-chloro-2,3'-bipyridin-5-yl)-1-(pyridin-3 5 ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]methyl}methylcarbamate (431 mg), (6-chloropyridin-3 yl)boronic acid (237 mg), sodium hydrogencarbonate (252 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added 10 to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 900C for 3 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. 15 The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1->3:7), and fractions showing Rf value of 0.6 (eluent: hexane-ethyl 20 acetate=1:1) were collected to give the title compound of Reference Example 172 as a colorless oil (yield 100 mg, 22%). Then, fractions showing Rf value of 0.4 (eluent: hexane-ethyl acetate=1:1) were collected to give the title compound of Reference Example 173 as a pale-yellow powder (yield 100 mg, 25 19%). Reference Example 172 'H-NMR (CDCl 3 )S: 1.47 (9H, s), 2.81 (3H, s), 4.23 (2H, s), 6.24 (1H, s), 7.23-7.38 (3H, m), 7.59-7.63 (1H, m), 7.72 (1H, dd, J=8.3, 2.3 Hz), 8.14 (1H, d, J=2.3 Hz), 8.64 (1H, d, J=2.3 Hz), 8.78 (1H, dd, J=4.7, 1.7 Hz). 30 Reference Example 173 1 H-NMR (CDCl 3 )5: 1.47 (9H, s), 2.82 (3H, s), 4.24 (2H, s), 6.29 (1H, s), 7.31-7.37 (2H, m), 7.47 (1H, d, J=8.3 Hz), 7.64-7.68 (1H, m), 7.76-7.86 (2H, m), 8.38 (1H, dd,.J=8.5, 2.5 Hz), 8.51 (1H, d, J=1.9 Hz), 8.63 (1H, d, J=2.3 Hz), 8.77 (1H, dd, J=4.9, 1.5 Hz), 9.04 (1H, d, J=2.3 Hz). 35 Reference Example 174 144 tert-butyl ({5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-3 yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate By a similar operation as in Reference Example 79 and using tert-butyl ({5-bromo-l-[(6-methoxypyridin-3 5 yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (463 mg), (2-fluoropyridin-3-yl)boronic acid (172 mg), sodium carbonate (260 mg) and tetrakis(triphenylphosphine)palladium (176 mg), the title compound was obtained as a pale-yellow oil (yield 293 mg, 45%). 10 1 H-NMR (CDCl 3 )5: 1.47 (9H, s), 2.83 (3H, brs), 3.97 (3H, s), 4.23 (2H, brs), 6.28 (1H, s), 6.69-6.72 (1H, m), 7.26-7.36 (2H, m), 7.49-7.53 (1H, m), 7.75-7.80 (1H, m), 8.22-8.23 (1H, m), 8.26-8.27 (1H, m). Reference Example 175 15 tert-butyl ({5-[2-fluoro-3-(hydroxymethyl)phenyl]-1-(pyridin 3-ylsulfonyl)-lH-pyrrol-3-yl}methyl)methylcarbamate To a solution of tert-butyl {[5-(2-fluoro-3 formylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3 yl]methyl}methylcarbamate (388 mg) in tetrahydrofuran (8 mL) 20 were added under ice-cooling, sodium borohydride (41.3 mg) and methanol (3 mL) . After stirring at the same temperature for 30 min, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and 25 concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane ethyl acetate=2:1->1:2) to give the title compound as a colorless oil (yield 238 mg, 61%). 'H-NMR (CDCl 3 )5: 1.46 (9H, s), 2.83 (3H, s), 4.24 (2H, brs), 3o 4.65 (2H, brs), 6.19 (1H, brs), 7.15-7.19 (2H, m), 7.34-7.38 (2H, m), 7.51-7.55 (1H, m), 7.73-7.76 (1H, m), 8.40-8.41 (1H, m), 8.75-8.77 (1H, m), 1H not detected. Reference Example 176 tert-butyl ({5-[2-fluoro-3-(1-hydroxyethyl)phenyl]-1-(pyridin 35 3-ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate 145 By a similar operation as in Reference Example 175 and using tert-butyl {[5-(3-acetyl-2-fluorophenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (443 mg), the title compound was obtained as a pale-yellow amorphous 5 form (yield 318 mg, 71%). 1 H-NMR (CDCl 3 )S: 1.47 (9H, s), 1.50 (3H, d, J=6.3 Hz), 2.83 (3H, s), 4.25 (2H, brs), 5.06 (1H, q, J=6.3 Hz), 6.20 (1H, brs), 7.09-7.22 (2H, m), 7.34-7.38 (2H, m), 7.59-7.64 (1H, m), 7.72-7.76 (1H, m), 8.40 (1H, d, J=2.4 Hz), 8.75-8.78 (1H, m), 10 1H not detected. Reference Example 177 tert-butyl {[5-(2-fluoro-3-methoxyphenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yllmethyl}methylcarbamate tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 15 3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-3 methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (88 mg) were added to a mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen 20 atmosphere 1000C for 2 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced 25 pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 475 mg, about 100%). 1 H-NMR (CDCl 3 )5: 1.46 (9H, s), 2.82 (3H, s), 3.90 (3H, s), 4.24 (2H, s), 6.21 (1H, d, J=1.5 Hz), 6.72-6.79 (1H, m), 7.00-7.09 3o (2H, m), 7.32-7.36 (2H, m), 7.69-7.73 (1H, m), 8.63 (1H, d, J=2.3 Hz), 8.76 (1H, dd, J=4.9, 1.5 Hz). Reference Example 178 tert-butyl {[5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate 35 tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-IH-pyrrol 146 3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-6 methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (176 mg) were added to a mixture of 1,2-dimethoxyethane (8 mL) and 5 water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 100C for 20 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried 10 over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 100 mg, 21%). 15 1 H-NMR (CDCl 3 )S: 1.46 (9H, s), 2.85 (3H, s), 3.58 (3H, s), 4.26 (2H, s), 6.17 (1H, d, J=1.9 Hz), 6.64-6.70 (2H, m), 7.31-7.39 (3H, m), 7.71-7.75 (1H, m), 8.60 (1H, d, J=1.9 Hz), 8.76 (1H, dd, J=4.9, 1.5 Hz). Reference Example 179 20 2-[4-(difluoromethoxy)phenyll-4,4,5,5-tetramethyl-1,3,2 dioxaborolane A solution (10 mL) of 1-bromo-4-(difluoromethoxy)benzene (500 mg), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2 dioxaborolane (654 mg), potassium acetate (660 mg) and 1,1' 25 bis(diphenylphosphino)ferrocene dichloropalladium (73.2 mg) in dimethylformamide was stirred at 800C for 3 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was washed with water and saturated brine, dried over anhydrous sodium 30 sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-+8:1) to give the title compound as a pale-yellow oil (yield 348 mg, 58%). 1 H-NMR .(CDCl 3 )5: 1.35 (12H, s), 6.54 (1H, t, J=73.5 Hz), 7.09 35 (2H, d, J=7.8 Hz), 7.81 (2H, d, J=7.8 Hz). 147 Reference Example 180 tert-butyl ({5-[4-(difluoromethoxy)phenyl]-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-lH-pyrrol 5 3-yl]methyl}methylcarbamate (430 mg), 2-[4 (difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2 dioxaborolane (348 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (174 mg) were suspended in dimethoxyethane (10 mL) and water (4 mL), and the mixture 10 was stirred under a nitrogen atmosphere at 1050C for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced 15 pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1-+2:1) to give the title compound as a pale-yellow oil (yield 550 mg, quantitative yield). 'H-NMR (CDCl 3 )S: 1.46 (9H, s), 2.80 (3H, s), 4.21 (2H, brs), 20 6.13 (1H, brs), 6.57 (1H, t, J=73.2 Hz), 7.06-7.09 (2H, m), 7.21-7.31 (4H, m), 7.55-7.59 (1H, m), 8.54 (1H, d, J=2.4 Hz), 8.71-8.73 (1H, m). Reference Example 181 tert-butyl methyl{[5-(4-methylpyridin-3-yl)-1-(pyridin-3 25 ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-lH-pyrrol 3-yllmethyl}methylcarbamate (431 mg), (4-methylpyridin-3 yl)boronic acid (206 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added 30 to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 800C for 6 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. 35 The extract was washed with saturated brine, dried over 148 anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1-+0:1) to give the title compound as a colorless oil (yield 230 mg, 52%). 5 1 H-NMR (CDCl 3 )5: 1.47 (9H, s), 2.11 (3H, s), 2.85 (3H, s), 4.27 (2H, s), 6.15 (1H, s), 7.18 (1H, d, J=4.9 Hz), 7.34-7.39 (2H, m), 7.58-7.62 (1H, m), 7.94 (1H, s), 8.49 (1H, d, J=5.3 Hz), 8.64 (1H, d, J=2.3 Hz), 8.80 (1H, dd, J=4.9, 1.5 Hz). Reference Example 182 10 3-bromo-2-methylpyridine 2-Methylpyridine (46.6 g) was added dropwise to aluminum chloride (200 g) and the mixture was stirred at 1000C. To a mixture was added dropwise bromine (40.0 g) at the same temperature over 1 hr, and the mixture was further stirred for 15 30 min. After cooling, the reaction mixture was poured into ice water, concentrated hydrochloric acid was added until the mixture was acidified. The obtained solution was washed with ethyl acetate, and the aqueous layer was basified with a 8 mol/L aqueous sodium hydroxide solution. After extraction with 20 diethyl ether, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-diethyl ether=10:1) to give the title compound as a colorless oil (yield 5.09 g, 25 12%). 1 H-NMR (CDCl 3 )S: 2.67 (3H, s), 6.98-7.03 (1H, m), 7.78-7.82 (1H, .m), 8.40-8.44 (1H, m). Reference Example 183 tert-butyl methyl{[5-(2-methylpyridin-3-yl)-1-(pyridin-3 30 ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate To a solution of 3-bromo-2-methylpyridine (504 mg) in diethyl ether (15 mL) was added a 1.62 mol/L solution (2 mL) of n-butyl lithium in hexane at -780C, and the mixture was stirred at the same temperature for 15 min. Thereto was added 35 triisopropoxyborane (1.22 mL) at the same temperature, and the 149 obtained mixture was stirred at 00C for 1 hr. Methanol (2 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. tert-Butyl ({5-bromo-l [(pyridin-3-yl)sulfonyl]-1IH-pyrrol-3-yl}methyl)methylcarbamate 5 (432 mg), sodium carbonate (1.15 g), tetrakis(triphenylphosphine)palladium (174 mg), 1,2 dimethoxyethane (20 mL) and water (10 mL) was added to the residue, and the mixture was stirred under a nitrogen atmosphere at 1050C for 1 hr. The reaction mixture was allowed 1o to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was l5 purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a brown oil (yield 282 mg, 22%). lH-NMR (CDCl 3 )S: 1.47 (9H, s), 2.09 (3H, s), 2.85 (3H, s), 4.27 (2H, brs), 6.14 (1H, brs), 7.10-7.14 (1H, m), 7.26-7.38 (3H, 20 m), 7.56-7.60 (1H, m), 8.54-8.56 (1H, m), 8.60-8.61 (lH, m), 8.78-8.80 (1H, m). Reference Example 184 6-methylnicotinamide A mixture of methyl 6-methylnicotinate (13.9 g) and 28% 25 aqueous ammonia (140 mL) was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 8.98 g, 72%). 1 H-NMR (CDCl 3 )S: 2.63 (3H, s), 5.60-6.20 (2H, brm), 7.25-7.28 30 (1H, m), 8.04-8.07 (1H, m), 8.90 (1H, d, J=2.1 Hz). Reference Example 185 6-methylpyridine-3-amine Bromine (1.0 mL) was added to a 4 mol/L aqueous sodium hydroxide solution (60 mL) at 0 0 C, and the mixture was stirred 35 at the same temperature for 15 min. 6-Methylnicotinamide (2.4 150 g) was added to the obtained solution over 10 min, and the mixture was stirred at room temperature for 30 min and further stirred at 750C for 4 hr. The reaction mixture was allowed to cool to room temperature, and extracted with ethyl 5 acetate:THF=2:1. The extract was washed with a small amount of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound as a pale-yellow solid (yield 0.93 g, 49%). 10 -H-NMR (CDCl 3 )S: 2.43 (3H, s), 3.54 (2H, brs), 6.89-6.95 (2H, m), 7.99-8.01 (1H, m). Reference Example 186 6-methylpyridin-3-ylsulfonyl chloride To a mixture of 6-methylpyridine-3-amine (449 mg) and 15 concentrated hydrochloric acid (5 mL) was added a solution of sodium nitrite (857 mg) in water (2 mL) at 00C, and the mixture was stirred at the same temperature for 10 min. To the mixture was added a solution of concentrated hydrochloric acid (2.5 mL), copper sulfate (69 mg) and sodium hydrogen sulfite (5.08 20 g) in water (8 mL) at 00C, and the mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified 25 by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1) to give the title compound as a pale-yellow solid (yield 0.12 g, 15%). H-NMR (CDCl 3 )S: 2.73 (3H, s), 7.40-7.43 (1H, m), 8.16-8.20 (iH, m), 9.11-9.12 (1H, m). 30 Reference Example 187 tert-butyl ({5-bromo-1-[(6-methylpyridin-3-yl)sulfonyl]-1H pyrrol-3-yl methyl)methylcarbamate To a solution of tert-butyl [(5-bromo-1H-pyrrol-3 yl)methyl]methylcarbamate (207 mg) in tetrahydrofuran (30 mL) 35 was added sodium hydride (60% in oil, 31 mg) at OOC, and the 151 mixture was stirred at the same temperature for 10 min. A solution (3 mL) of 15-crown-5 (0.16 mL) and 6-methylpyridin-3 ylsulfonyl chloride (117 mg) in tetrahydrofuran was added at the same temperature. After stirring at room temperature for 5 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The 1o residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a brown oil (yield 213 mg, 79%). 'H-NMR (CDCl 3 )6: 1.47 (9H, s), 2.66 (3H, s), 2.79 (3H, s), 4.17 (2H, brs), 6.26 (1H, brs), 7.26-7.33 (:2H, m), 8.03-8.07 (1H, 15 m), 9.01-9.02 (1H, m). Reference Example 188 tert-butyl ({5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3 yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate A suspension of tert-butyl ({5-bromo-1-[(6-methylpyridin 20 3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (206 mg), (2-fluoropyridin-3-yl)boronic acid (80 mg), sodium carbonate (119 mg) and tetrakis(triphenylphosphine)palladium (80 mg) in 1,2-dimethoxyethane (5 mL) and water (2.5 mL) was stirred under a nitrogen atmosphere at 1050C for 1 hr. The reaction 25 mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated 3o under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow oil (yield 87 mg, 41%).. 1 H-NMR (CDCl 3 )5: 1.46 (9H, s), 2.62 (3H, m), 2.82 (3H, s), 4.23 35 (2H, brs), 6.29 (1H, s), 7.18-7.27 (2H, m), 7.33 (1H, s), 152 7.54-7.57 (iH, m), 7.72-7.75 (1H, m), 8.26-8.27 (IH, m), 8.53 (1H, s). Reference Example 189 5-(2-fluoropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrole-3 5 carbaldehyde 5-Bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.15 g), (2-fluoropyridin-3-yl)boronic acid (2.83 g), sodium hydrogencarbonate (2.53 g) and tetrakis(triphenylphosphine)palladium (870 mg) were added to a 10 degassed mixture of 1,2-dimethoxyethane (80 mL) and water (20 mL), and the mixture was stirred under a nitrogen atmosphere at 800C for 5 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract 15 was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1-+*2:3) to give the title compound as a colorless oil (yield 2.25 g, 68%). 20 1H-NMR (CDCl 3 )5: 6.71 (1H, d, J=1.7 Hz), 7.24-7.28 (1H, m), 7.42-7.48 (4H, m), 7.62-7.68 (1H, m), 7.70-7.76 (1H, m), 8.14 (1H, d, J=1.9 Hz), 8.28-8.31 (1H, m), 9.90 (1H, s). Reference Example 190 5-(2-fluoropyridin-3-yl)-lH-pyrrole-3-carbaldehyde 25 5-(2-Fluoropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrole-3 carbaldehyde (2.25 g) was dissolved in methanol (20 mL) and tetrahydrofuran (20 mL), a 8 mol/L aqueous sodium hydroxide solution (20 mL) was added dropwise at room temperature and the mixture was stirred for 1 hr. The reaction mixture was 3o diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue and insoluble crystals were collected by 35 filtration to give the title compound as pale-brown crystals 153 (yield 1.03 g, 79%). H-NMR (DMSO-d 6 )5: 6.99 (1H, d, J=l.5 Hz), 7.43-7.48 (1H, m), 7.88 (1H, s), 8.12-8.15 (1H, m), 8.27-8.34 (1H, m), 9.77 (1H, s), 12.28 (1H, brs). 5 Reference Example 191 4-chloro-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde 5-(2-Fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (610 mg) was dissolved in N,N-dimethylformamide (20 mL), N chlorosuccinimide (641 mg) was added and the mixture was io stirred at 800C for 40 min. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column 15 chromatography (eluent: hexane-ethyl acetate=3:2-y1:1) to give the title compound as a colorless powder (yield 320 mg, 44%). 1 H-NMR (DMSO-d 6 )5: 7.49-7.54 (1H, m), 7.86 (1H, d, J=2.3 Hz), 8.12-8.19 (1H, m), 8.30-8.32 (1H, m), 9.80 (1H, s), 12.48 (1H, brs). 20 Reference Example 192 4-chloro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H pyrrole-3-carbaldehyde To a solution (20 mL) of 4-chloro-5-(2-fluoropyridin-3 yl)-1H-pyrrole-3-carbaldehyde (270 mg) in tetrahydrofuran was 25 added sodium hydride (60% in oil, 100 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (530 mg) was added dropwise and the mixture was stirred for 30 min. 3 Pyridylsulfonyl chloride (321 mg) was added, and the mixture was further stirred for 1 hr. The reaction mixture was diluted 30 with saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1->1:4), 35 and crystallized from diethyl ether to give the title compound 154 as colorless crystals (yield 358 mg, 81%). 'H-NMR (CDCl 3 )S: 7.35-7.39 (1H, m), 7.42-7.46 (1H, m), 7.69 7.73 (1H, m), 7.76-7.82 (1H, m), 8.14 (1H, s), 8.39-8.41 (1H, m), 8.64 (1H, dd, J=2.5 Hz, 0.6 Hz), 8.89 (1H, dd, J=4.8 Hz, 5 1.6 Hz), 9.97 (1H, s). Reference Example 193 tributyl(2-thienyl)stannane A solution (10 mL) of 2-bromothiophene (1.0 g) in tetrahydrofuran was cooled to -700C, and a 1.6 mol/L solution 10 (4.2 mL) of n-butyllithium in hexane was added dropwise. After stirring at the same temperature for 30 min, tributyltin chloride (2.1 g) was added dropwise. After further stirring for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was 15 washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual oil (2.4 g) containing the title compound was used for the next step without purification. Reference Example 194 20 tert-butyl methyl{[1-(pyridin-3-ylsulfonyl)-5-(2-thienyl)-lH pyrrol-3-yl]methyl}carbamate To a solution of crude tributyl(2-thienyl)stannane (1.1 g) and tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]methyl}methylcarbamate (430 mg) in toluene was 25 added tetrakis(triphenylphosphine)palladium (116 mg), and the mixture was stirred under a nitrogen atmosphere at 120 0 C for 1 hr. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column 30 chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a pale-yellow oil (yield 315 mg, 73%). 1 H-NMR (CDCl 3 )S: 1.47 (9H, s), 2.83 (3H, s), 4.22 (2H, brs), 6.25 (1H, brs), 7.04-7.07 (1H, m), 7.16-7.17 (1H, m), 7.27 7.31 (2H, m), 7.36-7.37 (1H, m), 7.62-7.66 (1H, m), 8.58-8.59 35 (1H, m), 8.71-8.73 (1H, m). 155 Reference Example 195, 3-methyl-2-(tributylstannyl)pyridine A solution (10 mL) of 2-bromo-3-methylpyridine (1.0 g) in tetrahydrofuran was cooled to -700C, and a 1.6 mol/L solution 5 (4.0 mL) of n-butyllithium in hexane was added dropwise. After stirring at the same temperature for 15 min, tributyltin chloride (2.2 g) was added dropwise. After further stirring for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was 10 washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1) to give the title compound as a colorless oil (yield 1.75 g, 79%). 15 1 H-NMR (CDCl 3 )5: 0.85-0.95 (9H, m), 1.11-1.17 (6H, m), 1.29 1.37 (6H, m), 1.49-1.57 (6H, m), 2.36 (3H, s), 6.99-7.03 (1H, m), 7.31-7.34 (1H, m), 8.52-8.54 (1H, m). Reference Example 196 tert-butyl methyl{[5-(3-methylpyridin-2-yl)-1-(pyridin-3 20 ylsulfonyl)-1H-pyrrol-3-yllmethyl}carbamate A solution of 3-methyl-2-(tributylstannyl)pyridine (1.0 g),.tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3 yl]methyl}methylcarbamate (563 mg) and tetrakis(triphenylphosphine)palladium (454 mg) in toluene was 25 stirred under a nitrogen atmosphere at 1200C for 30 hr. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless oil 30 (yield 129 mg, 22%). 1 H-NMR (CDCl 3 )S: 1.45 (9H, s), 2.80 (3H, brs), 4.25 (2H, brs), 6.26 (1H, brs), 7.23-7.27 (2H, m), 7.39-7.44 (1H, m), 7.60 (1H, d, J=6.9 Hz), 7.99-8.03 (1H, m), 8.36 (1H, d, J=4.5 Hz), 8.78-8.80 (1H, m), 8.86-8.87 (1H, m). 35 Reference Example 197 156 tert-butyl {[5-{2-fluoro-3-[(hydroxyimino)methyllphenyl}-1 (pyridin-3-ylsulfonyl) -lH-pyrrol-3-yl] methyl }methylcarbamate To a solution (3 mL) of tert-butyl {[5-(2-fluoro-3 formylphenyl)-1-(pyridin-3-ylsulfonyl)-1IH-pyrrol-3 5 yllmethyl}methylcarbamate (182 mg) in 2-propanol were added hydroxylamine hydrochloride (40 mg) and sodium acetate (47 mg). After stirring at room temperature for 3 hr, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was extracted with ethyl 10 acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1-+3:1) to give the title compound as a pale-yellow oil (yield 150 mg, 80%). 15 1H-NMR (CDCl 3 )8: 1.46 (9H, s), 2.82 (3H, s), 4.24 (2H, s), 6.22 (1H, s), 7.15-7.19 (2H, m), 7.31-7.35 (2H, m), 7.67-7.71 (1H, m), 7.76-7.85 (1H, m), 8.27 (1H, s), 8.63 (1H, d, J=2.1 Hz), 8.76-8.78 (1H, m), lH not detected. Reference Example 198 20 tert-butyl {[5-(3-cyano-2-fluorophenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl methyl}methylcarbamate To a solution (5 mL) of tert-butyl {[5-{2-fluoro-3 [(hydroxyimino)methyl]phenyl}-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yllmethyl}methylcarbamate (150 mg) in tetrahydrofuran 25 were added triethylamine (93 mg) and methanesulfonyl chloride (84 mg) at room temperature. The reaction mixture was stirred at 70 0 C for 8 hr, and cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous 30 sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1-+3:1) to give the title compound as a pale-yellow oil (yield 106 mg, 73%). 1 H-NMR (CDCl 3 )5: 1.46 (9H, s), 2.82 (3H, s), 4.24 (2H, s), 6.28 35 (1H, brs), 7.25-7.40 (3H, m), 7.48-7.53 (1H, m), 7.66-7.70 157 (2H, m), 8.62 (1H, d, J=2.7 Hz), 8.80-8.82 (1H, m). Reference Example 199 tert-butyl {[5-(4-bromo-3-thienyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl methyl}methylcarbamate 5 By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]methyl}methylcarbamate (430 mg), (4-bromo-3 thienyl)boronic acid (248 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (116 mg), the title 10 compound was obtained as a pale-yellow oil (yield 470 mg, 92%). 1 H-NMR (CDCls)6: 1.47 (9H, s), 2.84 (3H, brs), 4.26 (2H, brs), 6.21-6.22 (1H, m), 7.18-7.19 (1H, m), 7.30-7.39 (3H, m), 7.63 7.67 (1H, m), 8.57-8.58 (1H, m), 8.74-8.76 (1H, m). 15 Reference Example 200 tert-butyl {[5-(4-cyano-3-thienyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl methyl}methylcarbamate To a solution (5 mL) of tert-butyl {[5-(4-bromo-3 thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3 20 yljmethyl}methylcarbamate (470 mg) in N,N-dimethylformamide were added zinc cyanide (215 mg) and tetrakis(triphenylphosphine)palladium (212 mg) and the mixture was sufficiently degassed. The mixture was stirred with heating at 120 0 C for 18 hr and cooled to room temperature. 25. Water and ethyl acetate were added and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced 30 pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1->2:1) to give the title compound as a pale-yellow oil (yield 297 mg, 71%). 1 H-NMR (CDCl 3 )5: 1.47 (9H, s), 2.83 (3H, brs), 4.25 (2H, brs), 6.34-6.35 (1H, m), 7.35-7.39 (2H, m), 7.48 (1H, br), 7.65-7.68 35 (1H, m), 7.87 (1H, d, J=3.0 Hz), 8.53-8.54 (1H, m), 8.78-8.79 158 (1H, m). Example 1 N-methyl-i- 1[ 5-phenyl-1- (pyridin-3-ylsulfonyl) -1 H-pyrrol-3 yl methanamine dihydrochloride 5 5-Phenyl-l-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carbaldehyde (230 mg) was dissolved in absolute tetrahydrofuran (10 mL), a 2 mol/L solution (1 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was 10 added to a solution of sodium borohydride (76 mg) in methanol (5 mL), and the mixture was stirred at the same temperature for 20 min. The reaction mixture was diluted with ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and 15 dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate methanol=1:0-*1:1) and further by HPLC (ODS, 0.1% trifluoroacetic acid-containing water-0.1% trifluoroacetic 20 acid-containing acetonitrile=97:3-+0.1% trifluoroacetic acid containing acetonitrile) to give trifluoroacetate of the title compound. The obtained trifluoroacetate was neutralized with a saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed successively with a saturated 25 aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) and ethanol (5 mL) were 3o added, and the mixture was concentrated under reduced pressure and crystallized from ethyl acetate-ethanol to give the title compound (yield 85 mg, 29%). 1 H-NMR (DMSO-d 6 )S: 2.50 (3H, s), 3.97-4.00 (2H, s), 6.50 (1H, s), 7.14-7.16 (2H, m), 7.35-7.45 (3H, m), 7.62-7.70 (1H, m), 35 7.78-7.83 (2H, m), 8.47-8.48 (1H, m), 8.84-8.86 (1H, m), 9.08 159 (2H, br), 1H not detected. Example 2 1-{1-[(6-methoxypyridin-3-yl)sulfonyll-5-phenyl-1H-pyrrol-3 yl}-N-methylmethanamine hydrochloride 5 1-[(6-Methoxypyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole 3-carbaldehyde (59 mg) was dissolved in absolute tetrahydrofuran (5 mL), a 2 mol/L solution (0.25 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was 10 added to a solution of sodium borohydride (19 mg) in methanol (2 mL), and the mixture was stirred at the same temperature for 20 min. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was 15 evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate methanol=1:0-1:1) to give a free salt (48 mg) of the title compound. The obtained free salt was dissolved in ethyl acetate (2 mL), a 4 mol/L hydrogen chloride-ethyl acetate 20 solution (3 mL) was added, and the mixture was left standing at room temperature for 30 min. The precipitated crystals were collected by filtration, washed with ethyl acetate to give the title compound (yield 39 mg, 58%). 4H-NR (DMSO-d 6 )S: 2.50 (3H, s), 3.90 (3H, s), 3.98 (2H, s), 25 6.45 (1H, s), 6.91-6.94 (1H, m), 7.16-7.18 (2H, m), 7.36-7.45 (3H, m), 7.59-7.63 (1H, m), 7.72 (1H, s), 8.09-8.10 (1H, m), 8.91 (2H, br). Example 3 N-methyl-1-{1-[6-(methylamino)pyridin-3-ylsulfonyl]-5-phenyl 30 1H-pyrrol-3-yl methanamine dihydrochloride By a similar reaction as in Example 2 and using 1-(6 chloro-3-pyridinesulfonyl)-5-phenyl-lH-pyrrole-3-carbaldehyde (100 mg), the title compound was obtained (yield 58 mg, 47%). lH-NMR (DMSO-dG)S: 2.50 (3H, s), 2.78 (3H, s), 3.95-3.99 (2H, 35 m), 6.39-6.42 (2H, m), 7.20-7.23 (3H, m), 7.35-7.43 (3H, m), 160 7.63 (1H, s), 7.82-7.85 (2H, m), 9.00 (2H, br), 1H not detected. Example 4 N-methyl-1-{1-[2-(methylamino)pyridin-3-ylsulfonyl]-5-phenyl 5 1H-pyrrol-3-yl}methanamine dihydrochloride 1-(2-Chloropyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrole-3 carbaldehyde (173 mg) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution (1.25 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room 1o temperature for 12 hr. The reaction mixture was added to a solution (2 mL) of sodium borohydride (76 mg) in methanol, and the mixture was stirred at room temperature for 20 min. A saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract 15 was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate->ethyl acetate-methanol=1:4) to give a free salt of the title compound. To a solution (3 mL) of the 20 obtained free salt in ethanol was added a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL). The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 126 mg, 59%). 25 1 H-NMR (DMSO-d 6 )5: 2.50 (3H, s), 2.77 (3H, d, J=4.5 Hz), 3.95 3.99 (2H, m), 4.80 (1H, br), 6.28-6.30 (1H, m), 6.41-6.47 (2H, m), 7.10-7.19 (3H, m), 7.32-7.44 (3H, m), 7.88 (1H, s), 8.25 8.27 (1H, m), 9.19 (2H, br). Example 5 30 N-methyl-1-{1-[2-(methylamino)pyrimidin-3-ylsulfonyl]-5 phenyl-lH-pyrrol-3-yl}methanamine hydrochloride By a similar reaction as in Example 2 and using 1-(2 chloropyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrole-3 carbaldehyde (100 mg), the title compound was obtained (yield 35 64 mg, 57%). 161 'H-NMR (DMSO-d 6 )S: 2.50 (3H, s), 2.80-2.82 (3H, s), 3.98 (2H, s), 6.47 (1H, s), 7.23-7.26 (2H, m), 7.39-7.43 (3H, m), 7.66 7.67 (iH, m), 7.96-7.97 (1H, m), 8.11-8.12 (1H, m), 8.48-8.52 (1H, m), 8.97 (2H, br). 5 Example 6 N-methyl-1-[2-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]methanamine dihydrochloride By a similar reaction as in Example 2 and using 2-methyl 5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde lo (235 mg), an ethanol (1 equivalent) adduct of the title compound was obtained as a solid (yield 110 mg, 39%). 'H-NMR (DMSO-d 6 )5: 1.06 (3H, t, J=7.2 Hz), 2.43-2.50 (6H, m), 3.44 (2H, dd, J=14.1, 7.2 Hz), 3.91-3.94 (2H, m), 6.47 (1H, s), 7.21-7.43 (2H, m), 7.36-7.41 (3H, m), 7.56-7.63 (1H, m), 15 7.82-7.88 (1H, m), 8.53 (1H, s), 8.87-8.93 (3H, m), 2H not detected. Example 7 N-methyl-i-[l-(2-methylpyrimidin-5-ylsulfonyl)-5-phenyl-1H pyrrol-3-yl]-methanamine dihydrochloride 20 1-[(2-Methyl-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole 3-carbaldehyde (148 mg) was dissolved in absolute tetrahydrofuran (10 mL), a 2 mol/L solution (1.25 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred overnight at room temperature. The reaction mixture 25 was added to a solution of sodium borohydride (95 mg) in methanol (3.0 mL), and the mixture was stirred at the same temperature for 20 min. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated 30 under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), di-tert-butyl bicarbonate (0.55 g), sodium hydrogencarbonate (0.25 g) and water (10 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, 35 washed successively with a saturated aqueous sodium 162 hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), manganese dioxide (75% chemically 5 treated product, 1.5 g) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column Io chromatography (eluent: hexane-ethyl acetate=19:1-+1:1) to give an oil. The obtained oil was dissolved in ethanol (1 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure to give 15 a solid (67 mg). Recrystallization from ethanol gave the title compound as a colorless solid (yield 34 mg, 18%). 1H-NMR (DMSO-d 6 )S: 2.53 (3H, s), 2.70 (3H, s), 3.98 (2H, s), 6.50 (1H, s), 7.18-7.20 (2H, m), 7.38-7.47 (3H, m), 7.76-7.77 (1H, m), 8.59 (2H, s), 8.88 (2H, br), 1H not detected. 20 Example 8 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3 yl]-N-methylmethanamine fumarate 5-(2-Fluorophenyl)~1-(pyridin-3-ylsulfonyl)-lH-pyrrole-3 carbaldehyde (1.52 g) was dissolved in methanol (30 mL), a 40% 25 methylamine methanol solution (3.57 g) was added at room temperature and the mixture was stirred for 30 min. Sodium borohydride (523 mg) was added at room temperature and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (50 mL) was added and the mixture was stirred for 5 min. The 3o reaction mixture was basified with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel 35 column chromatography (eluent: ethyl acetate-methanol=1:0-+7:3) 163 to give a free salt of the title compound as a pale-yellow oil (yield 1.30 g) . The obtained free salt (750 mg) was dissolved in ethyl acetate (30 mL), a solution of fumaric acid (278 mg) in methanol (3 mL) was added dropwise at room temperature. 5 After stirring for 30 min, the obtained crystals were collected by filtration, and washed with ethyl acetate to give the title compound as colorless crystals (yield 912 mg, 74%). 'H-NMR (DMSO-d,)5: 2.43 (3H, s), 3.87 (2H, s), 6.47 (2H, s), 6.49 (1H, d, J=1.8 Hz), 7.07-7.13 (1H, m), 7.19-7.26 (2H, m), 10 7.49-7.56 (1H, m), 7.59-7.64 (1H, m), 7.74 (IH, d, J=1.8 Hz), 7.86-7.90 (iH, m), 8.56-8.57 (iH, m), 8.87-8.89 (1H, m), 3H not detected. melting point 201-2030C Example 9 15 N-methyl--{l-(pyridin-3-ylsulfonyl)-5-[2 (trifluoromethyl)phenyl]-1H-pyrrol-3-yl methanamine dihydrochloride 1-(Pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl] 1H-pyrrole-3-carbaldehyde (340 mg) was dissolved in ethanol 20 (34 mL), a 40% methylamine methanol solution (695 mg) was added at room temperature and the mixture was stirred for 30 min. Sodium borohydride (102 mg) was added at room temperature and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (10 mL) was added and the mixture was stirred for 5 min. 25 The reaction mixture was basified with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified 3o by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0-+7:3) and dissolved in ethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to 35 give the title compound as pale-red crystals (yield 288 mg, 164 69%). 'H-NMR (DMSO-d)S: 2.47 (3H, t, J=5.5 Hz), 4.00 (2H, t, J=5.5 Hz), 6.60 (iH, d, J=1.8 Hz), 7.18-7.21 (1H, m), 7.63-7.81 (4H, m), 7.91-8.00 (2H, m), 8.58 (1H, d, J=1.8 Hz), 8.90-8.92 (1H, 5 m), 9.48-9.57 (2H, m), 1H not detected. Example 10 N-methyl-1-[4-methyl-5-phenyl-l-(pyridin-3-ylsulfonyl)-1H pyrrol-3-ylmethanamine dihydrochloride By a similar reaction as in Example 2 and using 4-methyl 10 5-phenyl-l-(pyridin-3-ylsulfonyl)-iH-pyrrole-3-carbaldehyde (171 mg), the title compound was obtained (yield 110 mg, 50%). 'H-NMR (DMSO-d 6 )S: 1.79 (3H, s), 2.57 (3H, s), 3.96-4.00 (2H, m), 6.98-7.01 (2H, m), 7.36-7.43 (3H, m), 7.55-7.60 (1H, m), 7.79-7.82 (2H, m), 8.43-8.44 (1H, m), 8.84-8.86 (1H, m), 9.13 15 (2H, br), 1H not detected. Example 11 N-methyl-1-[4-methyl-5-phenyl-1-(pyridin-2-ylsulfonyl)-1H pyrrol-3-yl methanamine hydrochloride 4-Methyl-5-phenyl-1-(pyridin-2-ylsulfonyl)-lH-pyrrole-3 20 carbaldehyde (262 mg) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution (1.0 mL) of methylanine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was added to a solution (5 mL) of sodium borohydride (76 mg) in methanol, and 25 the mixture was stirred at room temperature for 20 min. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried. over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel 3o column chromatography (eluent: ethyl acetate-methanol=1:0-+1:1) and further by HPLC (ODS, 0.1% trifluoroacetic acid-containing water-0.1% trifluoroacetic acid-containing acetonitrile= 9 :1-+0.1% trifluoroacetic acid-containing acetonitrile) to give trifluoroacetate of the title compound. 35 The obtained trifluoroacetate was neutralized with a saturated 165 aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was 5 evaporated under reduced pressure. The residue was dissolved in ethyl acetate (3 mL), a 4 mol/L solution (2 mL) of hydrogen chloride in ethyl acetate was added. After allowing to stand at room temperature for 30 min, the precipitate was collected by filtration and washed with ethyl acetate to give the title lo compound (yield 141 mg, 47%). 1 H-NMR (DMSO-ds)5: 1.79 (3H, s), 2.59 (3H, s), 4.01 (2H, s), 6.88-6.90 (2H, m), 7.27-7.45 (4H, m), 7.71-7.74 (2H, m), 7.95 7.99 (1H, m), 8.68-8.70 (1H, m), 8.88 (2H, br). Example 12 15 1-{l-[(1,2-dimethyl-lH-imidazol-4-yl)sulfonyl)-4-methyl-5 phenyl-lH-pyrrol-3-yl}-N-methylmethanamine dihydrochloride 1-[(1,2-Dimethyl-IH-imidazol-4-yl)sulfonyll-4-methyl-5 phenyl-lH-pyrrole-3-carbaldehyde (294 mg) was dissolved in tetrahydrofuran (5 mL), a 2 mol/L solution (1.0 mL) of 20 methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hr. The mixture was heated to 400C, and the mixture was further stirred for 4 hr. The reaction mixture was added to a solution (5 mL) of sodium borohydride (76 mg) in methanol, and the mixture was stirred 25 at room temperature for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography 30 (eluent: hexane-ethyl acetate=9:1-->0:1) to give a free salt of the title compound. To a solution (3 mL) of the obtained free salt in ethyl acetate was added a 4 mol/L hydrogen chloride ethyl acetate solution (1 mL). After allowing to stand at room temperature for 30 min, the precipitate was collected by 35 filtration, and washed with ethyl acetate to give the title 166 compound (yield 196 mg, 53%). 1H-NMR (DMSO-d 6 )S: 1.79 (3H, s), 2.25 (3H, s), 2.60 (3H, m), 3.45 (3H, s), 3.95-3.99 (2H, m), 4.86 (1H, br), 6.99-7.01 (2H, m), 7.13 (1H, s), 7.32-7.39 (3H, m), 7.59 (1H, s), 8.96 (2H, 5 br). Example 13 1-{1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyll-4 methyl-5-phenyl-1H-pyrrol- 3 -yl}-N-methylmethanamine hydrochloride 10 By a similar reaction as in Example 12 and using 1-[(5 chloro-1,3-dimethyl-lH-pyrazol-4-yl)sulfonyl]-4-methyl-5 phenyl-1H-pyrrole-3-carbaldehyde (378 mg), the title compound was obtained as a solid (yield 238 mg, 55%). 1H-NMR (DMSO-d 6 )S: 1.67 (3H, s), 1.79 (3H, s), 2.58 (3H, s), 15 3.67 (3H, s), 3.99 (2H, s), 6.97-6.99 (2H, m), 7.33-7.41 (3H, m), 7.73 (1H, s), 8.90 (2H, br). Example 14 1-{1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-methyl-5 phenyl-1H-pyrrol-3-yl}-N-methylmethanamine hydrochloride 20 Using 1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4 yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (295 mg), a free salt (297 mg) of the compound of Example 13 was obtained as an oil. The obtained oil was dissolved in toluene (10 mL) and methanol (10 mL), 10% palladium carbon (50% 25 containing water, 30 mg) and 20% sodium ethoxide-ethanol solution (309 mg) were added, and the mixture was stirred at under a hydrogen atmosphere at room temperature for 24 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved 30 in ethyl acetate solution (5 mL) and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After allowing to stand at room temperature for 30 min, the precipitate was collected by filtration, and washed with ethyl acetate to give the title compound (yield 221 mg, 72%). 35 1 H-NMR (DMSO-d6)5: 1.80 (3H, s), 1.90 (3H, s), 2.59 (3H, m), 167 3.63 (3H, s), 3.99 (2H, s), 6.99-7.02 (2H, m), 7.35-7.40 (3H, m), 7.51 (1H, s), 7.66 (1H, s), 8.87 (2H, br). Example 15 1-{1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methyl-5 5 phenyl-1H-pyrrol-3-yl}-N-methylmethanamine trifluoroacetate To a solution (1 mL) of 1-[(2,4-dimethyl-1,3-thiazol-5 yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (27.7 mg) in tetrahydrofuran was added a 2 mol/L solution (0.1 mL) of methylamine in tetrahydrofuran, and the mixture was stirred 10 at room temperature for 2 hr. The reaction mixture was added to a solution (1 mL) of sodium borohydride (7.6 mg) in methanol, and the mixture was stirred at room temperature for 20 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was 15 washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (ODS, 0.1% trifluoroacetic acid-containing water-0.1% trifluoroacetic acid-containing 20 acetonitrile (97:3)-->0.1% trifluoroacetic acid-containing acetonitrile alone), and triturated with diisopropyl ether to give the title compound as a solid (yield 12.1 mg, 33%). 'H-NMR (DMSO-d 6 )S: 1.80 (3H, s), 2.06 (3H, s), 2.58 (3H, s), 2.62 (3H, s), 4.03 (2H, s), 7.05-7.07 (2H, m), 7.37-7.44 (3H, 25 m), 7.67 (1H, s), 8.62 (2H, br). Example 16 [5-(2-fluorophenyl)-4-methyl-i-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]-N-methylmethanamine hydrochloride To a solution of 5-(2-fluorophenyl)-4-methyl-1-(pyridin 3o 3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (382 mg) in methanol (5 mL) and tetrahydrofuran (2 mL) was added a 40% methylamine methanol solution (1.1 mL), and the mixture was stirred at room temperature for 4 hr. Sodium borohydride (51 mg) was added to the reaction mixture, and the mixture was further 35 stirred for 15 min. The reaction mixture was concentrated 168 under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate 5 solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate) to give a free salt of the title compound (yield 342 mg) . To a solution of the lo obtained free salt (336 mg) in ethanol (5 mL) was added a 4 mol/L hydrogen chloride-ethyl acetate solution (5.0 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title. 15 compound as white crystals (yield 197 mg, 46%). H-NMR (DMSO-d 6 )5: 1.76 (3H, s), 2.59 (3H, t, J=5.4 Hz), 4.01 (2H, t, J=5.4 Hz), 7.03-7.08 (1H, m), 7.21-7.28 (2H, m), 7.51 7.64 (2H, m), 7.82-7.86 (2H, m), 8.53 (1H, d, J=2.4 Hz), 8.80 8.89 (3H, m). 20 Example 17 1-[1-(2-chloropyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl) N-methylmethanamine hydrochloride To a solution (3 mL) of tert-butyl {[l-(2-chloro-3 pyridinesulfonyl)-5-phenyl-1H-pyrrol-3 25 yl]methyl}methylcarbamate (70 mg) in ethyl acetate was added a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to give the title 3o compound (yield 29 mg, 49%). 1 H-NMR (DMSO-ds)S: 2.56 (3H, s), 4.04 (2H, s), 6.48 (1H, s), 6.99-7.02 (2H, m), 7.25-7.36 (4H, m), 7.66-7.69 (1H, m), 7.83 (1H, s), 8.60-8.62 (1H, m), 8.79 (2H, br). Example 18 35 5- ({4- [ (methylamino)methyl] -2-phenyl-1H-pyrrol-1 169 yl}sulfonyl)pyrimidine-2-amine To a solution (4 mL) of 1-(2-chloropyrimidin-5 ylsulfonyl)-5-phenyl-1IH-pyrrole-3-carbaldehyde (139 mg) in tetrahydrofuran was added a 0.5 mol/L amonia-dioxane solution 5 (4 mL) . After stirring at room temperature for 1 hr, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 10 The residue was dissolved in a tetrahydrofuran (5 mL), a 2 mol/L solution (0.75 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred overnight at room temperature. The reaction mixture was added to a solution (2 mL) of sodium borohydride (38 mg) in methanol, and the mixture 15 was stirred at room temperature for 5 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 20 The residue was purified by HPLC (ODS, 0.1% trifluoroacetic acid-containing water-0.1% trifluoroacetic acid-containing acetonitrile=9:1->0.1% trifluoroacetic acid-containing acetonitrile) to give trifluoroacetate of the title compound. The obtained trifluoroacetate was neutralized with a saturated 25 aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and crystallized crystals 30 were washed with diisopropyl ether to give the title compound as a colorless solid (yield 23 mg, 17%). 1 H-NMR (DMSO-d,)5: 2.27 (3H, s), 3.52 (2H, s), 6.31 (1H, s), 7.26-7.40 (6H, m), 7.94 (2H, br), 8.00 (2H, s), 1H not detected. 35 Example 19 170 1-[ (imidazo[1,2-alpyrimidin-6-ylsulfonyl)-5-phenyl-1H-pyrrol 3-yl]-N-methylmethanamine dihydrochloride Under a nitrogen atmosphere, a solution of ethyl 1 (imidazo[1,2-a]pyrimidin-6-ylsulfonyl)-5-phenyl-lH-pyrrole-3 5 carboxylate (242 mg) in tetrahydrofuran (10 mL) was cooled to -780C, a 1.5 mol/L solution (2.0 mL) of diisobutylaluminum hydride in toluene was added with stirring. After stirring at the same temperature for 1 hr, the mixture was warmed to -20oC over 1 hr. Water (30 mL) was added and, after stirring at the 10 same temperature for 5 min, the mixture was allowed to warm to 00C over 10 min. Ethyl acetate (20 mL) was added and, after stirring at the same temperature for 15 min, the mixture was stirred at room temperature for 20 min. The reaction mixture in a gel state was filtered through celite, and celite was 15 washed with ethyl acetate. The organic layer was separated from the filtrate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 mL), manganese dioxide (75% chemically treated product, 2.0 g) 20 was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, the residue was dissolved in absolute tetrahydrofuran (5 mL), a 2 mol/L solution (0.6 25 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was added to a solution of sodium borohydride (45 mg) in methanol (2 mL), and the mixture was stirred at the same temperature for 20 min. The reaction mixture was diluted with 3o ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), di-tert-butyl bicarbonate (0.22 g), sodium hydrogencarbonate (84 mg) and water (5 mL) were added, 35 and the mixture was stirred at room temperature for 30 min. 171 The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), manganese 5 dioxide (75% chemically treated product, 1.0 g) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel 10 column chromatography (eluent: hexane-ethyl acetate=19:1->0:1) to give an oil. The obtained oil was dissolved in ethanol (1 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 2 hr, the solvent was evaporated under reduced pressure, and the is residue was triturated with ethyl acetate-ethanol to give the title compound as a brown solid (yield 8.5 mg, 3%). 1 H-NMR (DMSO-d 6 )5: 2.50 (3H, s), 4.02-4.05 (2H, m), 6.49 (1IH, s), 7.16-7.19 (2H, m), 7.32-7.44 (3H, m), 7.79 (1H, s), 7.92 7.99 (2H, m), 8.29-8.30 (1H, m), 8.97 (2H, br), 9.23-9.24 (1H, 20 m), 1H not detected. Example 20 N-methyl-l-[5-phenyl-l-(pyridazin-3-ylsulfonyl)-lH-pyrrol-3 yl methanamine fumarate Under a nitrogen atmosphere, a solution of ethyl 5 25 phenyl-1-(pyridazin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (567 mg) in tetrahydrofuran (16 mL) was cooled to -780C, a 1.5 mol/L solution (6.4 mL) of diisobutylaluminum hydride in toluene was added with stirring. The reaction mixture warmed to -200C over 1 hr. Water (75 mL) was added, and after 30 stirring at the same temperature for 5 min, the mixture was allowed to warm to 00C over 10 min. Ethyl acetate (75 mL) was added, and after stirring at the same temperature for 15 min, the.mixture was stirred at room temperature for 20 min. The reaction mixture was filtered through celite, and celite was 35 washed with ethyl acetate. The organic layer was separated 172 from the filtrate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), manganese dioxide (75% chemically treated product, 5.0 g) 5 was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was dissolved in absolute tetrahydrofuran (15 mL). A 2 mol/L 10 solution (1.5 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred overnight at room temperature. The reaction mixture was added to a solution of sodium borohydride (66 mg) in methanol (5 mL), and the mixture was stirred at the same temperature for 20 min. A saturated aqueous sodium 15 hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by HPLC (ODS, 0.1% 20 trifluoroacetic acid-containing water-0.1% trifluoroacetic acid-containing acetonitrile=9:1-+0.1% trifluoroacetic acid containing acetonitrile) to give trifluoroacetate of the title compound. The obtained trifluoroacetate was neutralized with a saturated aqueous sodium hydrogencarbonate solution, extracted 25 with ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a free salt (59 mg) of the title compound. The obtained free salt (59 mg) was 3o dissolved in methanol (2 mL) and ethyl acetate (2 mL), and fumaric acid (21 mg) was added. The solvent was evaporated under reduced pressure, and recrystallization from ethyl acetate-methanol gave the title compound as a pale-yellow solid (yield 41 mg, 6%). 35 1H-NMR (DMSO-d 6 )S: 2.42 (3H, s), 3.82 (2H, s), 6.41 (1H, s), 173 6.47 (2H, s), 7.09-7.12 (2H, m), 7.29-7.38 (3H, m), 7.63 (1H, s), 7.80-7.83 (1H, m), 7.91-7.96 (1H, m), 9.48-9.50 (1H, m), 3H not detected. Example 21 5 N-methyl-1-[1-(5-methyl-3-pyridinesulfonyl)-5-phenyl-1H pyrrol-3-yl]methanamine fumarate To a solution (5 mL) of tert-butyl {[1-(6-chloro-5 methyl-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3 yl]methyl}methylcarbamate (237 mg) in tetrahydrofuran was lo added hydrazine (160 mg) at room temperature with stirring. After stirring at the same temperature for 3 hr, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous 15 magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), manganese dioxide (75% chemically treated product, 1.0 g) was added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was filtered through celite, and 20 celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane ethyl acetate=19:1->1:1) to give an oil. The obtained oil was dissolved in ethanol (2 mL), and a 4 mol/L hydrogen chloride 25 ethyl acetate solution (1 mL) was added. After stirring at room temperature for 2 hr, the solvent was evaporated under reduced pressure, a saturated aqueous'sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated 3o brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue (93 mg) was dissolved in ethanol (3 mL), and fumaric acid (29 mg) was added. After allowing to stand at room temperature for 30 min, the precipitated crystals were collected by filtration and 35 washed with methanol to give the title compound as a colorless 174 solid (yield 91 mg, 40%). 'H-NMR (DMSO-d,)S: 2.27 (3H, s), 2.38 (3H, s), 3.75 (2H, s), 6.37 (1H, s), 6.47 (2H, s), 7.15-7.17 (2H, m), 7.36-7.45 (4H, m), 7.58 (1H, s), 8.28 (1H, s), 8.68 (1H,-s), 3H not detected. 5 Example 22 5-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1 yl}sulfonyl)pyridin-2-ol hydrochloride tert-Butyl {[1-(6-chloro-3-pyridinesulfonyl)-5-phenyl-IH pyrrol-3-yl]methyl}methylcarbamate (175 mg) was dissolved in 10 tetrahydrofuran (10 mL), a 8 mol/L aqueous sodium hydroxide solution (3.8 mL) was added, and the mixture was stirred at 500C for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium 15 sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1->0:1) to give a free salt of the title compound. To a solution (1 mL) of the obtained free salt in ethanol was added a 4 mol/L hydrogen chloride-ethyl acetate 20 solution (2 mL). After stirring at room temperature for 4 hr, the solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to give the title compound (yield 40 mg, 27%). 1 H-NMR (DMSO-d 6 )5: 2.50 (3H, s), 3.97-4.01 (2H, m), 6.32-6.36 25 (1H, m), 6.47 (1H, s), 7.20-7.23 (4H, m), 7.37-7.48 (3H, m), 7.66 (1H, s), 8.94 (2H, br), 12.35 (1H, br). Example 23 5-({4-[(methylamino)methyl]-2-phenyl-lH-pyrrol-1 yl}sulfonyl)pyridine-2-carbonitrile hydrochloride 30 Under an argon atmosphere, a mixture of tert-butyl {[1 (6-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3 yl]methyl}methylcarbamate (100 mg), zinc (II) cyanide (51 mg), tetrakis(triphenylphosphine)palladium (50 mg) and N,N dimethylformamide (4 mL) was stirred at 1000C for 2 hr. The 35 reaction mixture was diluted with ethyl acetate, washed 175 successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel 5 column chromatography (eluent: hexane-ethyl acetate=19:1-+7:3) to give an oil. The obtained oil was dissolved in ethyl acetate (2 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 1 hr, the solvent was evaporated under reduced pressure, 10 and the residue was crystallized from ethanol to give the title compound (yield 57 mg, 68%). 1H-NMR (DMSO-d 6 )S: 2.50 (3H, s), 3.98 (2H, s), 6.52 (1H, s), 7.15-7.17 (2H, m), 7.37-7.47 (3H, m), 7.79 (1H, s), 8.04-8.07 (1H, m), 8.22-8.24 (1H, m), 8.61-8.62 (1H, m), 9.03 (2H, br). 15 Example 24 N-methyl-1-{1-[(6-methylpyridin-3-yl)sulfonyll-5-phenyl-iH pyrrol-3-yllmethanamine dihydrochloride tert-Butyl ({[1-(6-methylpyridin-3-yl)sulfonyl]-5-phenyl 1H-pyrrol-3-yl}methyl)methylcarbamate (113 mg) was dissolved 20 in ethanol (2 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 40 mg, 38%). 25 1H-NNR (DMSO-d 6 )S: 2.50-2.53 (6H, m), 3.97-3.99 (2H, m), 6.46 (1H, s), 7.16-7.18 (2H, m), 7.38-7.44 (4H, m), 7.65-7.75 (2H, m), 8.34 (1H, s), 8.98 (2H, br), 1H not detected. Example 25 N-methyl-1-[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-1H-pyrrol 30 3-yl]methanamine hydrochloride By a similar operation as in Example 24 and using tert butyl {[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3 yl]methyl}methylcarbamate (182 mg), the title compound was obtained as colorless crystals (yield 64 mg, 41%). 35 1 H-NMR (CDCl 3 )S: 2.60 (3H, s), 3.98 (2H, brs), 6.57 (1H, brs), 176 7.00 (1H, brd, J=4.5 Hz), 7.16 (1H, brs), 7.26-7.31 (2H, m), 7.70 (2H, brs), 8.61 (1H, brs), 8.73 (1H, brs), 9.86 (2H, brs). Example 26 5 1-[5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3 yl]-N-methylmethanamine dihydrochloride tert-Butyl {[5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl]methyl}methylcarbamate (293 mg) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was 2o added at 00C, and the mixture was stirred at room temperature for 3 hr. The reaction solution was basified by adding dropwise to a 6% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous 15 sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1-+1:9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (5 mL), a 4 mol/L hydrogen 20 chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give the title compound as colorless crystals (yield 110 mg, 40%). 1 H-NMR (DMSO-d,)S: 2.47-2.51 (3H, m), 3.97 (2H, t, J=6.0 Hz), 25 6.52-6.53 (1H, m), 7.15-7.26 (4H, m), 7.57-7.61 (1H, m), 7.79 7.85 (2H, m), 8.00 (1H, d, J=2.4 Hz), 8.85-8.87 (1H, m), 9.22 (2H, br), 1H not detected. Example 27 N-methyl-i-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H 3o pyrrol-3-yl]methanamine dihydrochloride By a similar operation as in Example 26 and using tert butyl methyl{[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]methyl}carbamate (210 mg), the title compound was obtained as colorless crystals (yield 67 mg, 34%). More 35 specifically, tert-butyl methyl{[5-(2-methylphenyl)-1 177 (pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methylIcarbamate (210 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added at OOC, and the mixture was stirred at room temperature for 2 hr. The reaction solution was basified 5 by adding dropwise to a 6% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column lo chromatography (eluent: hexane-ethyl acetate=1:1-1:9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced 15 pressure. The residue was recrystallized from ethyl acetate ethanol to give the title compound as colorless crystals (yield 67 mg, 34%). H-NMR (DMSO-d 6 )S: 1.80 (3H, s), 2.49-2.53 (3H, m), 4.00 (2H, t, J=5.4 Hz), 6.46 (1H, d, J=2.4 Hz), 6.83 (1H, d, J=7.8 Hz), 20 7.13-7.22 (2H, m), 7.33-7.39 (1H, m), 7.59-7.63 (1H, m), 7.80 7.85 (2H, m), 8.46 (1H, d, J=2.4 Hz), 8.88-8.90 (1H, m), 9.27 (2H, br), 1H not detected. melting point 196-2000C Example 28 25 1-[5-(4-fluoro-2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]-N-methylmethanamine dihydrochloride By a similar operation as in Example 26 and using tert butyl {[5-(4-fluoro-2-methylphenyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl]methyl}methylcarbamate (216 mg), the title 3o compound was obtained as colorless crystals (yield 81 mg, 40%). 1 H-NMR (DMSO-d 6 )S: 1.80 (3H, s), 2.49-2.51 (3H, m), 4.00 (2H, t, J=6.0 Hz), 6.47 (1H, d, J=2.1 Hz), 6.85-6.90 (1H, m), 6.98 7.12 (2H, m), 7.61-7.65 (1H, m), 7.81-7.88 (2H, m), 8.51 (1H, 35 d, J=2.7 Hz), 8.89-8.91 (1H, m), 9.29 (2H, br), 1H not 178 detected. Example 29 N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl]methanamine dihydrochloride 5 By a similar operation as in Example 26 and using tert butyl methyl{[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl]methyl}carbamate (200 mg), the title compound was obtained as colorless crystals (yield 125 mg, 67%). More specifically, tert-butyl methyl{[5-(4-methyl-3-thienyl)-1 10 (pyridin-3-ylsulfonyl)-lH-pyrrol-3-yllmethyl}carbamate (200 mg) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added at 0OC, and the mixture was stirred at room temperature for 1 hr. The reaction solution was basified by adding dropwise to a 6% aqueous sodium hydrogencarbonate 15 solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1-41:9) to give 20 a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate 25 ethanol to give the title compound as colorless crystals (yield 125 mg, 67%). 1 H-NMR (DMSO-d 6 )S: 1.71 (3H, s), 2.49-2.51 (3H, m), 3.98 (2H, t, J=5.7 Hz), 6.49 (1H, d, J=2.1 Hz), 7.16-7.23 (2H, m), 7.58 7.62 (1H, m), 7.79-7.86 (2H, m), 8.50-8.51 (1H, m), 8.87-8.89 3o (1H, m), 9.30 (2H, br), 1H not detected. melting point 178-1810C Example 30 3-[4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H pyrrole-2-yl]benzonitrile hydrochloride 35 By a similar operation as in Example 26 and using tert 179 butyl {[5-(3-cyanophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]methyl}methylcarbamate (298 mg), the title compound was obtained as colorless crystals (yield 132 mg, 52%). 'H-NMR (DMSO-d)5: 2.48-2.51 (3H, m), 3.98 (2H, brs), 6.65 (1H, 5 d, J=1.8 Hz), 7.51-7.65 (4H, m), 7.85-7.95 (3H, m), 8.55 (1H, d, J=2.4 Hz), 8.88-8.90 (1H, m), 9.25 (2H, br). Example 31 1-[5-(2-chlorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3 yl]-N-methylmethanamine dihydrochloride 10 By a similar operation as in Example 26 and using tert butyl {[5-(2-chlorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yllmethyl}methylcarbamate (171 mg), the title compound was obtained as colorless crystals (yield 74 mg, 46%). 'H-NMR (DMSO-d,)S: 2.50 (3H, br), 4.01 (2H, t, J=6.0 Hz), 5.40 15 (1H, br), 6.55 (1H, d, J=2.1 Hz), 7.13-7.16 (1H, m), 7.35-7.40 (1H, m), 7.47-7.51 (2H, m), 7.61-7.65 (1H, m), 7.84-7.93 (2H, m), 8.57 (1H, d, J=2.1 Hz), 8.89-8.91 (1H, m), 9.23 (2H, br). Example 32 1-[5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 20 3-yl]-N-methylmethanamine dihydrochloride By a similar operation as in Example 26 and using tert butyl {[5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]methyl}methylcarbamate (110 mg), the title compound was obtained as colorless crystals (yield 58 mg, 25 56%). 1 H-NMR (DMSO-d 6 )S: 2.48-2.51 (3H, m), 3.98 (2H, t, J=5.7 Hz), 6.62 (1H, d, J=1.8 Hz), 7.13-7.17 (2H, m), 7.28-7.36 (1H, m), 7.62-7.66 (1H, m), 7.86-7.95 (2H, m), 8.61 (1H, d, J=2.4 Hz), 8.89-8.91 (1H, m), 9.31 (2H, br), 1H not detected. 30 Example 33 1-[5-(2,5-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]-N-methylmethanamine hydrochloride . By a similar operation as in Example 26 and using tert butyl {[5-(2,5-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H 35 pyrrol-3-yl]methyl}methylcarbamate (105 mg), the title 180 compound was obtained as colorless crystals (yield 39 mg, 43%). H-NMR (DMSO-d,)5: 2.50-2.51 (3H, m), 3.99 (2H, brs), 6.62 (1H, d, J=1.8 Hz), 7.00-7.06 (1H, m), 7.27-7.44 (2H, m), 7.63-7.67 5 (1H, m), 7.86 (1H, br), 7.94-7.97 (1H, m), 8.65 (1H, d, J=2.7 Hz), 8.90-8.92 (1H, m), 9.08 (2H, m). Example 34 1-[5-(4-chloro-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]-N-methylmethanamine dihydrochloride 10 By a similar operation as in Example 26 and using tert butyl {[5-(4-chloro-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl]methyl}methylcarbnate (103 mg), the title compound was obtained as colorless crystals (yield 32 mg, 33%). 15 1 H-NMR (DMSO-d,)5: 2.47-2.52 (3H, m), 3.97 (2H, t, J=6.0 Hz), 5.10 (1H, br), 6.64 (1H, brs), 7.15 (1H, t, J=7.8 Hz), 7.34 7.36 (1H, m), 7.50-7.53 (1H, m), 7.62-7.67 (1H, m), 7.88 (1H, brs), 7.95-7.98 (1H, m), 8.64 (1H, d, J=2.4 Hz), 8.90 (1H, d, J=4.8 Hz), 9.33 (2H, br). 20 Example 35 1-[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3 yl]-N-methylmethanamine hydrochloride tert-Butyl {[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl]methyl}methylcarbamate (280 mg) was dissolved 25 in ethyl acetate (3 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction solution was basified by adding dropwise to a 6% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with 30 ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate hexane=1:1-+9:1) to give a free salt of the title compound as a 35 pale-yellow oil. The obtained free salt was dissolved in ethyl 181 acetate, a 4 mol/L hydrogen chloride-ethyl acetate solution was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate and hexane, and recrystallized from ethyl acetate-ethanol to give 5 the title compound as colorless crystals (yield 84 mg, 35%). 'H-NMR (DMSO-d,)S: 2.49-2.51 (3H, m), 3.97 (2H, s), 6.57 (1H, d, J=1.8 Hz), 6.98-7.02 (2H, m), 7.27-7.33 (1H, m), 7.40-7.47 (1H, m), 7.58-7.62 (1H, m), 7.80-7.87 (2H, m), 8.54 (IH, d, J=2.7 Hz), 8.86-8.88 (1H, m), 9.06 (2H, br). l0 Example 36 1-[5-(2-fluorophenyl)-2-methyl-1-(pyridin-3-ylsulfonyl)-lH pyrrol-3-yl]-N-methylmethanamine fumarate A suspension of tert-butyl {[5-bromo-2-methyl-1-(pyridin 3-ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate (369 mg), 15 (2-fluorophenyl)boronic acid (234 mg), sodium carbonate (265 mg) and tetrakis(triphenylphosphine)palladium (48.9 mg) in 1,2-dimethoxyethane (15 mL) and water (7.5 mL) was stirred at 1050C for 12 hr. The reaction mixture was allowed to cool to room temperature, water was added and the mixture was 20 extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 25 hexane-ethyl acetate=1:4) to give an oil. The obtained oil was dissolved in ethanol (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was so neutralized by adding a saturated aqueous sodium hydrogencarbonate solution (50 mL). The mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the 35 solvent was evaporated under reduced pressure. The residue was 182 purified by basic silica gel column chromatography (eluent: ethyl acetate), and further by HPLC (ODS, 0.1% trifluoroacetic acid-containing water-0.1% trifluoroacetic acid-containing acetonitrile=9:1->O.1% trifluoroacetic acid-containing 5 acetonitrile) to give trifluoroacetate of the title compound. The obtained trifluoroacetate was neutralized with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate lo solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a free salt of the title compound (yield 65 mg). The free salt (62 mg) was dissolved in ethyl acetate (2 mL), a solution of fumaric acid (17 mg) in methanol (2 mL) was 15 added, and the mixture was stirred for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as white crystals (yield 25 mg, 7%). 1 H-NMR (DMSO-d,)5: 2.35 (3H, s), 2.40 (3H, s), 3.75 (2H, s), 20 6.46 (3H, s), 7.20-7.28 (3H, s), 7.44-7.52 (1H, m), 7.63-7.67 (1H, m), 7.88-7.92 (1H, m), 8.61 (1H, d, J=2.4 Hz), 8.88-8.90 (1H, m), 3H not detected. Example 37 N-methyl-i-(5-phenyl-l-{[5-(trifluoromethyl)pyridin-3 25 yl]sulfonyl)-lH-pyrrol-3-yl)methanamine hydrochloride To a solution of 5-phenyl-l-{[5-(trifluoromethyl)pyridin 3-yl]sulfonyl}-1H-pyrrole-3-carbaldehyde (137 mg) in absolute tetrahydrofuran (5 mL) was added at room temperature, a 2 mol/L solution (0.36 mL) of methylamine in tetrahydrofuran was 3o added, and the mixture was stirred for 16 hr. Sodium borohydride (27 mg) and methanol (2 mL) were added, and the mixture was stirred at the same temperature for 2 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with 35 ethyl acetate. The extract was washed with saturated brine, 183 dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), di-tert-butyl bicarbonate (218 mg), water (2 mL) and sodium hydrogencarbonate (84 mg) were added, and the mixture 5 was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran 10 (20 mL), manganese dioxide (75% chemically treated product, 1.0 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the 25 residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-+1:1), fractions containing a material showing Rf value of 0.46 (eluent:hexane-ethyl acetate=3:1) by TLC analysis were collected and concentrated under reduced pressure. The residue was dissolved in ethanol 20 (1 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 2 hr, the solvent was evaporated under reduced pressure. The residue was purified by HPLC (ODS, 0.1% trifluoroacetic acid containing water-0.1% trifluoroacetic acid-containing 25 acetonitrile=97:3-+0.1% trifluoroacetic acid-containing acetonitrile) to give trifluoroacetate of the title compound. The obtained trifluoroacetate was neutralized with a saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed successively with a saturated aqueous 30 sodium hydrogencarbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated 35 under reduced pressure. Recrystallization from ethanol gave 184 the title compound (yield 23 mg, 15%). 1 H-NMR (DMSO-d 6 )5: 2.50 (3H, s), 3.97 (2H, s), 6.49 (1H, s), 7.13-7.15 (2H, m), 7.37-7.48 (3H, m), 7.80-7.87 (2H, m), 8.72 (2H, br), 8.86 (1H, s), 9.33 (1H, s). 5 Example 38 N-methyl-1-{I-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H pyrrol-3-yl}methanamine dihydrochloride By a similar reaction as in Example 12 and using 1-[(2 methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3 10 carbaldehyde (180 mg), the title compound was obtained as a solid (yield 110 mg, 48%). 1 H-NMR (DMSO-d)S: 2.37 (3H, s), 2.53-2.57 (3H, m), 4.02-4.10 (2H, m), 6.51 (1H, d, J=1.8 Hz), 7.01 (2H, d, J=6.9 Hz), 7.11 7.35 (4H, m), 7.44-7.46 (1H, m), 7.84 (1H, d, J=2.1 Hz), 8.61 15 8.62 (1H, m), 9.07 (2H, br), 1H not detected. Example 39 1-[5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol 3-yl]-N-methylmethanamine fumarate 5-(2,6-Difluorophenyl)-1-(pyridin-3-ylsulfonyl)-iH 20 pyrrole-3-carbaldehyde (250 mg) was added to a mixture of a 40% methylanine methanol solution (560 mg) and methanol (5 mL) at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (41 mg) was added to the reaction mixture and the mixture was stirred for 10 min. The reaction mixture 25 was concentrated under reduced pressure at 300C. The residue was extracted with a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue 30 was purified by basic silica gel column chromatography (eluent: ethyl acetate), dissolved in ethanol (5 mL), and a solution of fumaric acid (84 mg) in ethanol (5 nL) was added to allow crystallization to give the title compound as colorless crystals (yield 229 mg, 67%). 35 1 H-NMR (DMSO-d 6 )S: 2.43 (3H, s), 3.85 (2H, s), 6.48 (2H, s), 185 6.57 (1H, d, J=1.7 Hz), 7.12-7.18 (2H, m), 7.55-7.66 (2H, m), 7.81 (1H, d, J=1.7 Hz), 7.93-7.97 (1H, m), 8.61 (1H, d, J=2.1 Hz), 8.90 (1H, dd, J=4.7, 1.5 Hz), 3H not detected. Example 40 5 1-[5-(4-cyclohexylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]-N-methylmethanamine dihydrochloride To a solution of 5-(4-cyclohexylphenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.78 g) in methanol (20 mL) were added methylammonium chloride (1.61 g) and sodium 10 cyanoborohydride (0.49 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was 15 washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=3:2->0:1) to give an oil (0.39 g). The oil was dissolved in ethyl acetate (3 mL), a 4 mol/L 20 hydrogen chloride-ethyl acetate solution (1.5 mL) was added, and the mixture was concentrated under reduced pressure. Crystallization from methanol-ethyl acetate gave the title compound as crystals (yield 0.41 g, 43%). 1 H-NMR (DMSO-d 6 )S: 1.20-1.46 (5H, m), 1.68-1.88 (5H, m), 2.45 25 2.59 (1H, m), 2.48 (3H, s), 3.97 (2H, d, J=5.3 Hz), 6.48 (1H, s), 7.04 (2H, d, J=8.1 Hz), 7.20 (2H, d, J=8.1 Hz), 7.51-7.57 (1H, m), 7.73-7.79 (2H, m), 8.43 (1H, s), 8.83 (1H, d, J=4.7 Hz), 9.17 (2H, s), 1H not detected. Example 41 30 1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-lH-pyrrol-3-yll N-methylmethanamine dihydrochloride By a similar reaction as in Example 12 and using 4 fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carbaldehyde (121 mg), the title compound was obtained as a 35 colorless solid (yield 30.7 mg, 20%) . More specifically, 4 186 fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carbaldehyde (121 mg) was dissolved in tetrahydrofuran (5 mL), a 2 mol/L solution (0.22 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 5 4 hr. A solution (2 mL) of sodium borohydride (28 mg) in methanol was added to the reaction mixture, and the mixture was stirred at room temperature for 20 min. A aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with 10 saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by. silica gel column chromatography (eluent: ethyl acetate-->ethyl acetate-methanol=1:4) to give a free salt of the title compound. To a solution (2 mL) of the obtained free salt 15 in ethanol was added a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL). After allowing to stand at room temperature for 30 min, the mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a colorless solid (yield 30.7 mg, 20 20%). 'H-NMR (DMSO-d)5: 2.56-2.59 (3H, m), 4.03-4.05 (2H, m), 7.14 7.16 (2H, m), 7.41-7.48 (3H, m), 7.53-7.62 (1H, m), 7.80-7.85 (2H, m), 8.50 (1H, d, J=2.4 Hz), 8.88-8.89 (1H, m), 9.07 (2H, br), 1H not detected. 25 melting point 201-2030C Example 42 1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl] N-methylmethanamine 4-Fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 30 carbaldehyde (0.27 g) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution (0.8 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hr. Sodium borohydride (91 mg) and methanol (7 mL) were added, and the mixture was stirred at the same 35 temperature for further 30 min. The reaction mixture was 187 concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under 5 reduced pressure. The residue was purified by basic silica gel column chromatography (hexane-ethyl acetate=19:1-+0:1). The above-mentioned operation was repeated to give the title compound (0.22 g, yield 39%) as a colorless solid. 1 H-NMR (CDCl 3 )5: 2.48 (3H, s), 3.63 (2H, s), 7.22-7.42 (7H, m), 10 7.56-7.60 (1H, m), 8.55 (1H, d, J=2.1 Hz), 8.73 (1H, dd, J=4.8, 1.8 Hz), 1H not detected. melting point 98-990C Example 43 1-[4-fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yll 15 N-methylmethanamine 0.5 fumarate 1-[4-Fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]-N-methylmethanamine (32 mg) was dissolved in ethanol (2 mL), fumaric acid (10 mg) was added, and the mixture was stood at room temperature for -1 hr. The precipitate was collected by 20 filtration to give the title compound as a colorless solid (yield 16 mg, 42%). 'H-NMR (DMSO-d 6 )5: 2.30 (3H, s), 3.60 (2H, s), 6.50 (1H, s), 7.18-7.21 (2H, m), 7.39-7.50 (4H, m), 7.57-7.61 (1H, m), 7.79 7.83 (1H, m), 8.50 (1H, d, J=2.1 Hz), 8.87 (1H, dd, J=5.1, 1.8 25 Hz), 2H not detected. melting point 163-1660C Example 44 1-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-lH pyrrol-3-yl}-N-methylmethanamine dihydrochloride 30 By a similar reaction as in Example 12 and using 5-(2 fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyll-lH-pyrrole-3 carbaldehyde (134 mg), the title compound was obtained as a colorless solid (yield 96.1 mg, 57%) . More specifically, 5-(2 fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyll-1H-pyrrole-3 35 carbaldehyde (134 mg) was dissolved in tetrahydrofuran (10 188 mL), a 2 mol/L solution (0.6 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 4 hr. A solution (5 mL) of sodium borohydride (76 mg) in methanol was added to the reaction mixture, and the 5 mixture was stirred at room temperature for 20 min. An aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified 1o by silica gel column chromatography (eluent: ethyl acetate-*ethyl acetate-methanol=1:4) to give a free salt of the title compound. To a solution (2 mL) of the obtained free salt in ethanol was added a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL). After allowing to stand at room temperature 15 for 30 min, the mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a colorless solid (yield 96.1 mg, 57%). 'H-NMR (DMSO-d 6 )5: 2.50-2.56 (6H, m), 3.97-4.02 (2H, m), 6.55 20 (1H, d, J=1.8 Hz), 7.08-7.11 (1H, m), 7.22-7.26 (2H, m), 7.47 7.60 (2H, m), 7.76-7.82 (2H, m), 8.44 (1H, d, J=2.4 Hz), 9.04 (2H, br), 1H not detected. melting point 212-2130C Example 45 25 1-[5-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrol-3 yl]-N-methylmethanamine hydrochloride By a similar reaction as in Example 12 and using 5-(2 fluorophenyl)-1-(pyridin-2-ylsulfonyl)-lH-pyrrole-3 carbaldehyde (183 mg), the title compound was obtained as a 3o colorless solid (yield 78.3 mg, 37%). 1 H-NMR (DMSO-d)5: 2.54 (3H, s), 4.02 (2H, s), 6.52 (1H, d, J=2.1 Hz), 7.00-7.04 (1H, m), 7.11-7.19 (2H, m), 7.46-7.51 (1H, m), 7.57-7.60 (IH, m), 7.74-7.78 (2H, m), 8.03-8.08 (1H, m), 8.70-8.85 (3H, m). 35 Example 46 189 1-(5-(2-fluorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl] 1H-pyrrol-3-yl}-N-methylmethanamine fumarate To a solution (3 mL) of 5-(2-fluorophenyl)-1-[(l-methyl 1H-pyrazol-4-yl)sulfonyll-lH-pyrrole-3-carbaldehyde (217 mg) 5 in tetrahydrofuran were added a 40% methylamine methanol solution (152 mg) and methanol (1 mL) at room temperature. After stirring at room temperature for 1 hr, sodium borohydride (82 mg) was added at OC. After stirring at room temperature for 30 min, water was added and the mixture was 10 extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane ethyl acetate=1:1->1:9) to give a free salt of the title 15 compound as a pale-yellow oil (yield 152 mg) . A solution of the obtained free salt in ethyl acetate (5 mL) was added to a solution of fumaric acid (50.6 mg) in methanol (1 mL), and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol/water=95/5 to give the title 20 compound as colorless crystals (yield 143 mg, 48%). 'H-NMR (DMSO-d 6 )S: 2.46 (3H, s), 3.82 (3H, s), 3.85 (2H, s), 6.41 (1H, d, J=1.8 Hz), 6.46 (2H, s), 7.15-7.26 (3H, m), 7.46 7.56 (3H, m), 8.11 (1H, s), 3H not detected. Example 47 25 N-methyl--1[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yllmethanamine fumarate To a solution of 5-(2-methylphenyl)-l-(pyridin-3 ylsulfonyl)-lH-pyrrole-3-carbaldehyde (521 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) was added a 40% 30 methylamine methanol solution (373 mg). After stirring at room temperature for 1 hr, sodium borohydride (202 mg) was added. After stirring at the same temperature for 30 min, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous 35 sodium sulfate, and concentrated under reduced pressure. The 190 residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1->1:9) to give a free salt of the title compound as a yellow oil (yield 422 mg). A solution of the obtained free salt in ethanol (5 mL) was added to a 5 solution (15 mL) of fumaric acid (144 mg) in ethanol, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 414 mg, 56%). 'H-NMR (DMSO-dE)S: 1.81 (3H, s), 2.45 (3H, s), 3.88 (2H, s), 10 6.33 (1H, d, J=1.8 Hz), 6.46 (2H, s), 6.83-6.85 (1H, m), 7.12 7.22 (2H, m), 7.32-7.37 (1H, m), 7.57-7.61 (1H, m), 7.69 (1H, d, J=1.8 Hz), 7.78-7.82 (1H, m), 8.44-8.45 (1H, m), 8.87-8.89 (1H, m), 3H not detected. melting point 207-2100C 15 Example 48 1-[4-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]-N-methylmethanamine fumarate To a solution of 4-chloro-5-(2-fluorophenyl)-1-(pyridin 3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (429 mg) in 20 tetrahydrofuran (5 mL) and methanol (3 mL) was added a 40% methylamine methanol solution (275 mg) at room temperature. After stirring for 30 min, sodium borohydride (99 mg) was added. After stirring at the same temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. 25 The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1-+1:9) to give a free salt of the title compound as a yellow oil (yield 257 3o mg). A solution of the obtained free salt in ethyl acetate (5 mL) was added to a solution (10 mL) of fumaric acid (79 mg) in methanol, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 216 mg, 36%). 35 1 H-NMR (DMSO-de)S: 2.43 (3H, s), 3.75 (2H, s), 6.54 (2H, s), 191 7.13-7.19 (1H, m), 7.24-7.32 (2H, m), 7.55-7.66 (2H, m), 7.81 (1H, s), 7.88-7.92 (1H, m), 8.56-8.57 (1H, m), 8.90-8.92 (1H, m), 3H not detected. Example 49 5 1-[4-fluoro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]-N-methylmethanaine fumarate To a solution of 4-fluoro-5-(2-fluorophenyl)-l-(pyridin 3-ylsulfonyl)pyrrole-3-carbaldehyde (0.60 g) in tetrahydrofuran (6 mL) and methanol (6 mL) was added a 40% 1o methylamine methanol solution (1.8 mL) and the mixture was stirred at room temperature for 30 min. Sodium borohydride (84 mg) was added at room temperature and the mixture was stirred for 5 min and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the 15 residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column 20 chromatography (eluent: ethyl acetate) to give a free salt of the title compound as a pale-yellow oil (yield 0.36 g). The obtained free salt (0.36 g) was dissolved in ethanol (10 mL), and a solution of fumaric acid (0.12 g) in ethanol (10 mL) was added at room temperature. The reaction mixture was stirred 25 for 14 hr, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 0.73 g, 43%). 'H-NMR (DMSO-d 6 )S: 2.36 (3H, s), 3.69 (2H, s), 6.54 (2H, s), 7.21-7.32 (3H, m), 7.54-7.65 (3H, m), 7.86-7.90 (1H, m), 8.57 30 (1H, d, J=2.4 Hz), 8.89-8.91 (1H, m), 3H not detected. Example 50 1-[4-fluoro-5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]-N-methylmethanamine fumarate To a solution (5 mL) of 4-fluoro-5-(2-methylphenyl)-l 35 (pyridin-3-ylsulfonyl)pyrrole-3-carbaldehyde (0.45 g) in 192 tetrahydrofuran were added a 40% methylamine methanol solution (1.5 mL) and methanol (5 mL) and the mixture was stirred at room temperature for 30 min. Sodium borohydride (76 mg) was added at room temperature and the mixture was stirred for 30 5 min and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried 10 over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate) to give a free salt of the title compound as a pale-yellow oil (yield 0.33 g). The obtained free salt (0.33 g) was dissolved in ethanol (4 mL), 15 and a solution of fumaric acid (0.10 g) in ethanol (10 mL) was added at room temperature. After stirring for 30 min, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 0.32 g, 54%). 20 'H-NMR (DMSO-d 6 )S: 1.76 (3H, s), 2.43 (3H, s), 3.80 (2H, s), 6.52 (2H, s), 6.97-6.99 (1H, m), 7.19-7.26 (2H, m), 7.37-7.42 (1H, m), 7.58-7.65 (2H, m), 7.80-7.84 (1H, m), 7.46 (1H, d, J=2.4 Hz), 8.89-8.91 (1H, m), 3H not detected. Example 51 25 1-[2-chloro-5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl]-N-methylmethanamine fumarate 2-chloro-5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrole-3-carbaldehyde (160 mg) was added to a mixture of 40% methylamine methanol solution (325 mg) and methanol (20 30 mL) at room temperature. After stirring for 30 min, sodium borohydride (48 mg) was added and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure at 300C. The residue was extracted with a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. 35 The extract was washed with saturated brine, dried over 193 anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=1:0->7:3) and dissolved in ethanol (2 mL), and a solution of fumaric acid 5 (48 mg) in ethanol (2 mL) was added. Crystallization from the mixture gave the title compound as colorless crystals (yield 29 mg, 14%). 1 H-NMR (DMSO-d 6 )6: 2.28 (3H, s), 3.65 (2H, s), 6.51 (2H, s), 6.73 (1H, s), 7.21-7.28 (2H, m), 7.55-7.65 (1H, m), 7.73-7.77 10 (1H, m), 8.08-8.12 (1H, m), 8.82 (1H, d, J=2.4 Hz), 8.96 (iH, dd, J=4.9, 1.5 Hz), 3H not detected. Example 52 1-[2-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]-N-methylmethanamine fumarate 15 To a solution of methylamine hydrochloride (232 mg) in methanol (10 mL) was added 2-chloro-5-(2-fluorophenyl)-1 (pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde (250 mg) and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (218 mg) was added and the mixture was 20 stirred for 2 hr. The reaction mixture was concentrated under reduced pressure at 300C and extracted with a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 25 The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=1:0-->17:3) and dissolved in ethyl acetate (10 mL), and a solution of fumaric acid (80 mg) in methanol (2 mL) was added. Crystallization from the mixture gave the title compound as colorless crystals (yield 97 mg, 3o 29%). 'H-NMR (DMSO-dE)6: 2.23 (3H, s), 3.61 (2H, s), 6.51 (2H, s), 6.61 (1H, s), 7.27-7.33 (2H, m), 7.43-7.56 (2H, m), 7.69-7.74 (1H, m), 8.02-8.06 (1H, m), 8.80 (1H, brs), 8.94 (1H, dd, J=4.8, 1.4 Hz), 3H not detected. 35 Example 53 194 1-{1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl} N-methylmethanamine hydrochloride tert-Butyl ({1-[(5-bromopyridin-3-yl)sulfonyl)-5-phenyl 3-yl-lH-pyrrol-3-yl}methyl)methylcarbamate (120 mg) was 5 dissolved in ethanol (3 mL), and a 4 mol/L hydrogen chloride ethyl acetate solution (1 mL) was added. After stirring at room temperature for 4 hr, the mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a solid (yield 51.3 mg, 10 49%). 'H-NMR (DMSO-d 6 )6: 2.50 (3H, s), 3.96 (2H, m), 6.51 (1H, s), 7.15-7.17 (2H, m), 7.39-7.50 (3H, m), 7.77 (1H, s), 7.84 (1H, s), 8.48 (1H, s), 8.89 (:2H, br), 9.03 (1H, s). Example 54 15 5-({4-[(methylamino)methyl]-2-phenyl-lH-pyrrol-l yl}sulfonyl)nicotinonitrile hydrochloride A mixture of tert-butyl ({1-[(5-bromopyridin-3 yl)sulfonyll-5-phenyl-3-yl-lH-pyrrol-3 yl}methyl)methylcarbamate (112 mg), zinc cyanide (50 mg) and 20 N,N-dimethylformamide (4 mL) was degassed with argon gas. Tetrakis(triphenylphosphine)palladium (46 mg) was added, and the mixture was stirred at 100 0 C for 1.5 hr. After cooling the reaction mixture to room temperature, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture 25 was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-3:2) to give a colorless oil. The obtained oil 30 was dissolved in ethanol (2 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 1 hr, the mixture was concentrated under reduced pressure, and recrystallized from ethanol to give the title compound as a solid (yield 32.7 mg, 35 42%). 195 'H-NMR (DMSO-d 6 )6: 2.50-2.52 (3H, m), 3.98 (2H, s), 6.50 (1H, s), 7.13-7.16 (2H, m), 7.37-7.50 (3H, m), 7.76 (1H, d, J=1.8 Hz), 8.28 (1H, d, J=2.1 Hz), 8.66 (1H, d, J=2.4 Hz), 8.82 (2H, br), 9.31 (1H, d, J=2.1 Hz). 5 Example 55 methyl 5-({4-[(methylamino)methyll-2-phenyl-lH-pyrrol-1 yl}sulfonyl)nicotinate hydrochloride A mixture of tert-butyl ({1-[(5-bromopyridin-3 yl)sulfonyl]-5-phenyl-3-yl-1H-pyrrol-3 10 yl}methyl)methylcarbamate (112 mg), dichloro[bis(triphenylphosphine)]palladium (28 mg), triethylamine (0.25 mL) and methanol (15 mL) was stirred under a carbon monoxide atmosphere (3 atm) at 1000C for 12 hr. After cooling to room temperature, the reaction mixture was 15 concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 20 The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1->3:2) to give a colorless oil. The obtained oil was dissolved in ethanol (2 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 1 hr, the 25 mixture was concentrated under reduced pressure, and recrystallized from ethanol to give the title compound as a solid (yield 47.0 mg, 56%). 1 H-NMR (DMSO-ds)8: 2.49-2.51 (3H, m), 3.91 (3H, s), 3.98 (2H, s), 6.50 (1H, d, J=1.8 Hz), 7.15-7.17 (2H, m), 7.37-7.50 (3H, 3o m), 7.80 (1H, s), 7.93-7.94 (1H, m), 8.81 (1H, d, J=2.1 Hz), 8.91 (2H, br), 9.29 (1H, d, J=2.1 Hz). Example 56 N-methyl-1-{1-[(5-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H pyrrol-3-yl}methanamine dihydrochloride 35 Under an argon atmosphere, a mixture of tert-butyl ({1 196 [(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-3-yl-lH-pyrrol-3 yl}methyl)methylcarbamate (112 mg), methylboronic acid (18 mg), tetrakis(triphenylphosphine)palladium (23 mg), potassium carbonate (138 mg) and 1,4-dioxane (5 mL) was stirred at 800C 5 for one day. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified 10 by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1->1:1) to give an oil. The oil was dissolved in ethanol (1 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 1 hr, the mixture was concentrated under reduced pressure. 15 The residue was recrystallized from ethanol-ethyl acetate to give the title compound as a colorless solid (yield 32.6 mg, 39%). 'H-NMR (DMSO-d 6 )5: 2.28 (3H, s), 2.50-2.53 (3H, m), 3.94-4.00 (2H, m), 6.48 (1H, d, J=1.8 Hz), 7.12-7.15 (2H, m), 7.37-7.52 20 (4H, m), 7.75 (1H, s), 8.29 (1H, d, J=2.1 Hz), 8.70 (1H, d, J=1.5 Hz), 9.08 (2H, br), 1H not detected. Example 57 1-[5-(2,4-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol 3-yl]-N-methylmethanamine hydrochloride 25 By a similar operation as in Example 33 and using tert butyl {[5-(2,4-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-lH pyrrol-3-yllmethyl}methylcarbamate (177 mg), the title compound was obtained as colorless crystals (yield 68 mg, 45%). 30 'H-NMR (DMSO-d)S: 1.76 (3H, s), 2.32 (3H, s), 2.49 (3H, s), 3.99 (2H, s), 6.38 (1H, d, J=1.8 Hz), 6.71 (1H, d, J=8.1 Hz), 6.95-7.03 (2H, m), 7.59-7.63 (1H, m), 7.77-7.85 (2H, m), 8.48 (iH, d, J=2.7 Hz), 8.88-8.90 (1H, m), 9.07 (2H, br). Example 58 35 N-methyl-i-{5-[4-(methylsulfonyl)phenyl]-1-(pyridin-3 197 ylsulfonyl)-1H-pyrrol-3-yl}methanamine dihydrochloride To a solution of tert-butyl methyl{[5-[4 (methylsulfonyl)phenyll-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3 yllmethyl}carbamate (275 mg) in ethyl acetate (2 mL) was added 5 a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 4 hr. The precipitated crystals were collected by filtration, washed with ethyl acetate and recrystallized from ethanol to give the title compound as white crystals (yield 157 mg, 33%). 10 'H-NMR (DMSO-d 6 )S: 2.50 (3H, s), 3.29 (3H, s), 3.98 (2H, t, J=5.6 Hz), 6.67 (1H, d, J=1.9 Hz), 7.48 (2H, d, J=8.7 Hz), 7.60 (1H, dd, J=8.6, 4.4 Hz), 7.86-7.97 (4H, m), 8.59 (1H, d, J=1.9 Hz), 8.88 (1H, dd, J=4.8, 1.4 Hz), 9.20 (2H, s), 1H not detected. 15 Example 59 (2-{4- [ (methylamino)methyl]-1- (pyridin-3-ylsulfonyl) -1H pyrrole-2-yl}phenyl)methanol fumarate tert-Butyl ({5-[2-(hydroxymethyl)phenyl]-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate (132 mg) was 20 dissolved in trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was basified with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium 25 sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0- 9 :1) to give a free salt of the title compound as a colorless oil (yield 60.3 mg). A solution of the obtained free salt in ethyl 30 acetate (5 mL) was added to a solution of fumaric acid (19.6 mg) in methanol (2 mL), and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 48 mg, 35%). 35 'H-NMR (DMSO-d 6 )S: 2.42 (3H, s), 3.83 (2H, s), 4.00 (2H, s), 198 6.35 (1H, d, J=1.5 Hz), 6.46 (2H, S), 6.81-6.83 (1H, m), 7.17 7.22 (1H, m), 7.41-7.50 (2H, m), 7.55-7.60 (1H, m), 7.65 (1H, s), 7.75-7.78 (1H, m), 8.46 (1H, d, J=2.4 Hz), 8.86 (1H, d, J=4.8 Hz), 4H not detected. 5 Example 60 N-methyl-i-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl]methanamine fumarate By a similar reaction as in Example 59 and using tert butyl {[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H 10 pyrrol-3-yl]methyl}methylcarbamate (943 mg), the title compound was obtained as colorless crystals (yield 553 mg, 57%). More specifically, tert-butyl {[5-(4-methyl-3-thienyl) 1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (943 mg) was dissolved in trifluoroacetic acid (3 mL), and the 15 mixture was stirred at room temperature for 30 min. The reaction mixture was basified with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and 'the solvent was 20 evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:9) to give a free salt of the title compound as a colorless oil (yield 631 mg) . A solution of the obtained free salt in ethyl acetate (5 mL) was added to a solution of 25 fumaric acid (211 mg) in methanol (2 mL), and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol-water to give the title compound as colorless crystals (yield 553 mg, 57%). 'H-NMR (DMSO-d 6 )5: 1.71 (3H, s), 2.42 (3H, s), 3.83 (2H, s), 3o 6.34 (1H, d, J=1.8 Hz), 6.45 (2H, s), 7.15-7.16 (1H, m), 7.21 7.22 (1H, m), 7.56-7.60 (1H, m), 7.64-7.65 (1H, m), 7.78-7.82 (1H, m), 8.48 (1H, d, J=2.4 Hz), 8.84-8.86 (1H, m), 3H not detected. melting point 182-1830C 35 Example 61 199 N-methyl-1- (5-phenyl-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3 yl)methanamine fumarate 5-Phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carbaldehyde (650 mg) was dissolved in a mixture of a 40% 5 methylamine methanol solution (808 mg) and methanol (30 mL) at room temperature and the mixture was stirred for 10 min. Sodium borohydride (118 mg) was addeg and the mixture was stirred for 10 min. The reaction mixture was concentrated under reduced pressure at 300C and the residue was extracted 10 with a saturated aqueous sodium hydrogencarbonate solution (40 mL) and ethyl acetate (80 mL). The extract was washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography 15 (eluent: ethyl acetate) and a solution of fumaric acid (242 mg) in ethanol (24 mL) was added. The obtained crystals were collected by filtration and recrystallized from ethanol-water (85:15) to give the title compound as colorless crystals (yield 480 mg, 52%). 20 'H-NMR (DMSO-d 6 )8: 2.42 (3H, s), 3.86 (2H, s), 6.42 (1H, d, J=1.9 Hz), 6.47 (2H, s), 7.14-7.18 (2H, m), 7.34-7.46 (3H, m), 7.54-7.58 (1H, m), 7.67 (1H, d, J=1.9 Hz), 7.76-7.80 (1H, m), 8.46 (1H, dd, J=2.5, 0.8 Hz), 8.84 (1H, dd, J=4.9, 1.5 Hz), 3H not detected. 25 Example 62 1-[5-mesityl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N methylmethanamine fumarate To a solution of 5-mesityl-1-(pyridin-3-ylsulfonyl)-lH pyrrole-3-carbaldehyde (0.37 g) in tetrahydrofuran (15 mL) was 30 added dropwise a solution of a 40% methylamine methanol solution (0.41 g) in tetrahydrofuran (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Methanol (10 mL) was added, and the mixture was further stirred at room temperature for 2 hr. Sodium borohydride (0.06 35 g) was gradually added under ice-cooling, and the mixture was 200 stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract 5 was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1->ethyl acetate-methanol=5: 1) to give a free salt of the title compound as a pale-brown oil. 10 To a solution of the obtained free salt in ethyl acetate (5 mL) was added dropwise a solution of fumaric acid (0.14 g) in methanol (2.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 min. The precipitate was collected by filtration and recrystallized from ethanol-water 15 to give the title compound as white crystals (yield 0.32 g, 61%). 'H-NMR (DMSO-d 6 )5: 1.58 (6H, s), 2.28 (3H, s), 2.44 (3H, s), 3.87 (2H, s), 6.21 (IH, s), 6.45 (2H, s), 6.83 (2H, s), 7.60 (1H, dd, J=8.1, 1.8 Hz), 7.70 (lH, s), 7.84 (1H, dd, J=8.4, 20 1.8 Hz), 8.46 (1H, s), 8.88 (1H, d, J=3.9 Hz), 3H not detected. Example 63 N-methyl-1-{5-[2-(methylthio)phenyll-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl}methanamine fumarate 25 To a solution (3 mL) of 5-[2-(methylthio)phenyl]-l (pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde (170 mg) in tetrahydrofuran were added a 40% methylamine methanol solution (110 mg) and methanol (1 mL) at room temperature, and the mixture was stirred for 1 hr. Sodium borohydride (59.8 mg) was 30 added under ice-cooling. After stirring at room temperature for 2 hr, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried.over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel 35 column chromatography (eluent: hexane-ethyl acetate=1:1->1:9) 201 to give a free salt of the title compound as a colorless oil. The obtained free salt was dissolved in ethyl acetate, and added to a solution (1 mL) of fumaric acid (33.2 mg) in methanol. The solvent was evaporated under reduced pressure, 5 and the residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 89.3 mg, 38%). 'H-NMR (DMSO-d6)S: 2.11 (3H, s), 2.43 (3H, s), 3.86 (2H, s), 6.38 (1H, d, J=1.8 Hz), 6.46 (2H, s), 7.07-7.20 (3H, m), 7.41 7.46 (1H, m), 7.53-7.58 (1H, m), 7.68 (1H, d, J=1.8 Hz), 7.79 io 7.83 (1H, m), 8.43 (1H, d, J=2.4 Hz), 8.82-8.84 (1H, m), 3H not detected. Example 64 N-methyl-1-{5-[2-(methylsulfonyl)phenyl]-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl methanamine 0.5 fumarate 15 By a similar operation as in Example 63 and using 5-[2 (methylsulfonyl)phenyll-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carbaldehyde (72.0 mg), the title compound was obtained as colorless crystals (yield 56.4 mg, 66%). 'H-NMR (DMSO-d6)S: 2.37 (3H, s), 3.00 (3H, s), 3.71 (2H, s), 20 6.41 (1H, s), 6.48 (1H, d, J=1.5 Hz), 7.14-7.17 (1H, m), 7.61 7.65 (2H, m), 7.70-7.80 (2H, m), 7.93-7.97 (1H, m), 8.02-8.05 (1H, m), 8.66 (1H, d, J=2.1 Hz), 8.87-8.89 (1H, m), 2H not detected. Example 65 25 2-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H pyrrole-2-yl}benzonitrile fumarate By a similar operation as in Example 63 and using 2-[4 formyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-2-yl]benzonitrile (129 mg), the title compound was obtained as colorless 30 crystals (yield 69 mg, 38%). 'H-NMR (DMSO-d 6 )S: 2.39 (3H, s), 3.82 (2H, s), 6.47 (2H, s), 6.58 (1H, d, J=1.8 Hz), 7.34-7.36 (1H, m), 7.59-7.76 (4H, m), 7.84.-7.89 (2H, m), 8.53 (1H, d, J=2.4 Hz), 8.87-8.89 (1H, m), 3H not detected. 35 Example 66 202 1-[5-(2,6-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 3-yl]-N-methylmethanamine fumarate To a solution of 5-(2,6-dimethylphenyl)-l-(pyridin-3 ylsulfonyl)-lH-pyrrole-3-carbaldehyde (0.42 g) in 5 tetrahydrofuran (15 mL) was added dropwise a solution of a 40% methylanine methanol solution (0.48 g) in tetrahydrofuran (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Methanol (10 mL) was added, and the mixture was further stirred at room temperature for 2 hr. 10 Sodium borohydride (0.07 g) was gradually added under ice cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was 15 extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane ethyl acetate=1:1-+ethyl acetate-methanol=5:1) to give a free 20 salt of the title compound as a pale-brown oil. To a solution of the obtained free salt in ethyl acetate (5 mL) was added dropwise a solution of fumaric acid (0.12 g) in methanol (2 mL) under ice-cooling and the mixture was stirred at room temperature for 15 min. The precipitate was collected by 25 filtration, and recrystallized from ethanol-water to give the title compound as white crystals (yield 0.18 g, 50%). 'H-NMR (DMSO-d 6 )5: 1.62 (6H, s)-, 2.45 (3H, s), 3.88 (2H, s), 6.25 (1H, d, J=1.5 Hz), 6.45 (2H, s), 7.02 (2H, d, J=7.5 Hz), 7.24 (1H, d, J=7.5 Hz), 7.58-7.62 (1H, m), 7.71 (1H, s), 7.81 3o 7.85 (1H, m), 8.44 (1H, d, J=2.7 Hz), 8.89 (1H, dd, J=4.8, 1.5 Hz), 3H not detected. Example 67 N-me.thyl-1-{5-[2-(methylsulfinyl)phenyll-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl}methanamine fumarate 35 To a suspension (5 mL) of sodium hydride (60% in oil, 203 39.5 mg) in tetrahydrofuran were added a solution (3 mL) of 5 [2-(methylsulfinyl)phenyl]-1H-pyrrole-3-carbaldehyde (160 mg) in N,N-dimethylformamide, 15-crown-5 (181 mg), and pyridin-3 ylsulfonyl chloride (134 mg) under ice-cooling. After stirring 5 at room temperature for 1 hr, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in tetrahydrofuran (5 mL), a 40% methylamine methanol solution 10 (160 mg) was added at room temperature and the mixture was stirred for 1 hr. Sodium borohydride (86.5 mg) was added under ice-cooling. After stirring at room temperature for 2 hr, water was added and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, dried 15 over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1: 1-ethyl acetate) to give a free salt of the title compound as a pale yellow oil. The obtained free salt was dissolved in ethyl 20 acetate, and added to a solution (1 mL) of fumaric acid (28.1 mg) in methanol. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 83.9 mg, 24%). 25 'H-NMR (DMSO-d,)S: 2.41 (3H, s), 2.49-2.51 (3H, m), 3.81 (2H, s), 6.46 (2H, s), 6.50 (1:H, d, J=1.5 Hz), 7.00 (1H, br), 7.50 8.00 (6H, m), 8.57 (1H, br), 8.87-8.89 (1H, m), 3H not detected. Example 68 3o 2-(2-fluorophenyl)-4-[(methylamino)methyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrole-3-carbonitrile fumarate 2-(2-Fluorophenyl)-4-formyl-1-(pyridin-3-ylsulfonyl)-1H pyrrole-3-carbonitrile (295 mg) was dissolved in a solution of methylamine hydrochloride (1.12 g) in methanol (20 mL) and the 35 mixture was stirred for 30 min. Sodium triacetoxyborohydride 204 (1.06 g) was added and the mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure at 300C, a saturated aqueous sodium hydrogencarbonate solution (40 mL) was added to the residue and the mixture was extracted 5 with ethyl acetate (80 mL) . The extract was washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=85:15->75:25), and then by basic silica 10 gel column chromatography (eluent: ethyl acetate), and a solution of fumaric acid (96 mg) in ethanol (5 mL) was added. Crystallization from the mixture gave the title compound as colorless crystals (yield 120 mg, 30%). IH-NMR (DMSO-d 6 )S: 2.40 (3H, s), 3.76 (2H, s), 6.57 (2H, s), 15 7.28-7.37 (3H, m), 7.63-7.71 (2H, m), 7.87 (1H, s), 7.95-7.99 (1H, m), 8.64 (1H, dd, J=2.5, 0.6 Hz), 8.94 (1H, dd, J=4.9, 1.5 Hz), 3H not detected. Example 69 5-(2-fluorophenyl)-3-[(methylamino)methyl-1-(pyridin-3 20 ylsulfonyl)-1H-pyrrole-2-carbonitrile fumarate 5-Phenyl-l-(pyridin-3-ylsulfonyl)-1H-pyrrole-3 carbaldehyde (650 mg) was dissolved in a mixture of a 40% methylamine methanol solution (808 mg) and methanol (30 mL) at room temperature and the mixture was stirred for 10 min. 25 Sodium borohydride (118 mg) was added and the mixture was stirred for 10 min. The reaction mixture was concentrated under reduced pressure at 300C, a saturated aqueous sodium hydrogencarbonate solution (40 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The 30 extract was washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate) and a solution of fumaric acid (242 mg) in ethanol (24 mL) was added. The 35 obtained crystals were collected by filtration, and 205 recrystallized from ethanol-water (85:15) to give the title compound as colorless crystals (yield 480 mg, 52%). H-NMR (DMSO-d 6 )5: 2.27 (3H, s), 3.74 (2H, s), 6.57 (2H, s), 6.71 (1H, s), 7.29-7.38 (3H, m), 7.58-7.64 (1H, m), 7.71-7.75 5 (1H, m), 7.96-8.00 (1H, m), 8.66 (1H, d, J=2.3 Hz), 8.97 (1H, dd, J=4.9, 1.5 Hz), 3H not detected. Example 70 4-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol 2-yl}benzonitrile fuarate 10 To a solution (2 mL) of tert-butyl {[5-(4-cyanophenyl)-1 (pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (382 mg) in ethyl acetate was added a 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) at room temperature. The mixture was stirred for 3 hr, and basified with a 15 saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography 20 (eluent: hexane-ethyl acetate=1:1->1:9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate, and added to a solution (2 mL) of fumaric acid (77.1 mg) in methanol. The solvent was evaporated under reduced pressure, and the residue was 25 recrystallized from a mixed solvent of ethanol and water to give the title compound as colorless crystals (yield 218 mg, 55%). 'H-NMR (DMSO-d 6 )6: 2.37 (3H, s), 3.79 (2H, s), 6.47 (2H, s), 6.55 (1H, d, J=1.8 Hz), 7.40-7.44 (2H, m), 7.55-7.60 (1H, m), 30 7.70-7.71 (1H, m), 7.81-7.87 (3H, m), 8.55-8.56 (1H, m), 8.84 8.86 (1H, m), 3H not detected. Example 71 4-fluoro-3-{4-[(methylanino)methyll-l-(pyridin-3-ylsulfonyl) 1H-pyrrol-2-yl}benzonitrile 0.5 fumarate 35 By a similar operation as in Example 70 and using tert 206 butyl {[5-(5-cyano-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yllmethyl}methylcarbamate (100 mg), the title compound was obtained as colorless crystals (yield 37.1 mg, 40%). 5 H-NMR (DMSO-d)5: 2.34 (3H, s), 3.71 (2H, s), 6.44 (1H, s), 6.55 (1H, brs), 7.52 (1H, t, J=9.0 Hz), 7.60-7.68 (2H, m), 7.73-7.75 (1H, m), 7.91-7.93 (1H, m), 8.03-8.08 (1H, m), 8.64 (1H, d, J=2.4 Hz), 8.88-8.90 (1H, m), 2H not detected. Example 72 10 1-[5-(2-fluoro-5-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]-N-methylmethanamine fumarate tert-Butyl {[5-(2-fluoro-5-methoxyphenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (475 mg) was dissolved in ethanol (10 mL), a 4 mol/L hydrogen chloride 15 ethyl acetate solution (2 mL) was added and the mixture was stirred at 700C for 30 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with 20 saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, added to a solution (13 mL) of fumaric acid (116 mg) in methanol, and the obtained crystals were collected by filtration to give the title compound as colorless crystals 25 (yield 385 mg, 78%). 'H-NMR (DMSO-d 6 )S: 2.41 (3H, s), 3.71 (3H, s), 3.82 (2H, s), 6.47 (1H, d, J=1.9 Hz), 6.48 (2H, s), 6.57-6.60 (1H, m), 7.02 7.07 (1H, m), 7.12-7.18 (1H, m), 7.60-7.64 (1H, m), 7.70 (1H, d, J=1.5 Hz), 7.89-7.93 (1H, m), 8.60 (1H, d, J=2.3 Hz), 8.88 30 (1H, dd, J=4.9, 1.5 Hz), 3H not detected. Example 73 1-(2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-2-yl}phenyl)ethanone fumarate By a similar operation as in Example 70 and using tert 35 butyl {[5-(3-acetyl-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl) 207 1H-pyrrol-3-yllmethyl}methylcarbamate (118 mg), the title compound was obtained as colorless crystals (yield 44.7 mg, 37%). 'H-NMR (DMSO-d 6 )S: 2.40 (3H, s), 2.49-2.53 (3H, m), 3.80 (2H, 5 m), 6.47 (2H, s), 6.52 (1H, d, J=1.8 Hz), 7.32-7.40 (2H, m), 7.59-7.64 (1H, m), 7.73 (1H, d, J=1.8 Hz), 7.86-7.93 (2H, m), 8.60 (1H, d, J=2.7 Hz), 8.87-8.89 (1H, m), 3H not detected. Example 74 1-[5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H 1o pyrrol-3-yl]-N-methylmethanamine fumarate To a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1 (pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (2.48 g) in ethyl acetate (10 mL) and methanol (10 mL) was added a 4 mol/L hydrogen chloride-ethyl acetate solution (20 15 mL) at room temperature. After stirring for 5 hr, the mixture was concentrated under reduced pressure. The residue was basified with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium 20 sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1->1:9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (10 mL) and added to a 25 solution of (10 mL) fumaric acid (350 mg) in methanol. The solvent was evaporated under reduced pressure and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as colorless crystals (yield 793 mg, 29%). 30 'H-NMR (DMSO-d 6 )5: 2.39 (3H, s), 3.78 (2H, s), 6.48 (2H, s), 6.56 (1H, d, J=1.8 Hz), 7.40-7.44 (1H, m), 7.61-7.65 (1H, m), 7.72-7.79 (2H, m), 7.89-7.93 (1H, m), 8.32-8.34 (1H, m), 8.62 (1H,. d, J=1.8 Hz), 8.88-8.90 (1H, m), 3H not detected. melting point 183-1840C 35 Example 75 208 1-[5-(3-fluoropyridin-4-yl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]-N-methylmethanamine fumarate tert-Butyl {[5-(3-fluoropyridin-4-yl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (60 mg) was 5 dissolved in methanol (5 mL), a 4 mol/L hydrogen chloride ethyl acetate solution (1.5 mL) was added and the mixture was stirred at 700C for 30 min. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium hydrogencarbonate solution was added. The mixture was 10 extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (8 mL), a solution of fumaric acid (58 mg) in methanol (2 mL) was added, and the obtained crystals were 15 collected by filtration to give the title compound as colorless crystals (yield 45 mg, 72%). 'H-NMR (DMSO-d 6 )S: 2.37 (3H, s), 3.78 (2H, s), 6.49 (2H, s), 6.64 (1H, d, J=1.5 Hz), 7.30-7.33 (1H, m), 7.62-7.66 (1H, m), 7.77 (1H, d, J=1.5 Hz), 7.94-7.98 (1H, m), 8.49-8.51 (1H, m), 20 8.64 (1H, d, J=1.5 Hz), 8.69 (1H, d, J=2.3 Hz), 8.90 (1H, dd, J=4.9, 1.5 Hz), 3H not detected. Example 76 1-[5-(2-chloropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl]-N-methylmethanamine fumarate 25 tert-Butyl {[5-(2-chloropyridin-3-yl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yllmethyl}methylcarbamate (280 mg) was dissolved in ethanol (10 mL), a 4 mol/L hydrogen chloride ethyl acetate solution (2 mL) was added and the mixture was stirred at 700C for 30 min. The reaction mixture was 30 concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL), a solution of 35 fumaric acid (116 mg) in methanol (3 mL) was added, and the 209 obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 197 mg, 68%). 'H-NMR (DMSO-d6)S: 2.40 (3H, s), 3.81 (2H, s), 6.49 (2H, s), 6.52 (1H, d, J=1.9 Hz), 7.47-7.52 (1H, m), 7.61-7.73 (3H, m), 5 7.90-7.94 (1H, m), 8.50 (1H, dd, J=4.9, 1.9 Hz), 8.63-8.64 (1H, m), 8.90 (1H, dd, J=4.5, 1.5 Hz), 3H not detected. Example 77 1-[5-(6-chloropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-lH pyrrol-3-yl]-N-methylmethanamine 1.5 fumarate 10 tert-butyl {[5-(6-chloropyridin-3-yl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg) was dissolved in methanol (8 mL), a 4 mol/L hydrogen chloride ethyl acetate solution (2 mL) was added and the mixture was stirred at 700C for 30 min. The reaction mixture was 15 concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography 20 (eluent: ethyl acetate-methanol=99:1->19:1) to give a free salt of the title compound. The obtained free salt was dissolved in ethyl acetate (8 mL), a solution of fumaric acid (116 mg) in methanol (2 mL) was added, and the obtained crystals were collected by filtration to give the title compound as 25 colorless crystals (yield 60 mg, 52%). 'H-NMR (DMSO-d6)S: 2.41 (3H, s), 3.83 (2H, s), 6.52 (3H, s), 6.58 (1H, d, J=1.5 Hz), 7.57-7.63 (2H, m), 7.75-7.78 (2H, m), 7.85-7.89 (1H, m), 8.20 (1H, d, J=2.3 Hz), 8.61 (1H, d, J=2.6 Hz), 8.88 (1H, dd, J=4.9, 1.5 Hz), 4H not detected. 30 Example 78 1-[5-(6'-chloro-2,3'-bipyridin-5-yl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl]-N-methylmethanamine 0.5 fumarate tert-Butyl {[5-(6'-chloro-2,3'-bipyridin-5-yl)-1 (pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate 35 (100 mg) was dissolved in ethanol (8 mL), a 4 mol/L hydrogen 210 chloride-ethyl acetate solution (2 mL) was added and the mixture was stirred at 700C for 30 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture 5 was extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=99:1-->19:1) to give a free salt of the title compound. The obtained free salt was dissolved in 10 ethyl acetate (8 mL), a solution of fumaric acid (116 mg) in methanol (2 mL) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 61 mg, 66%). 'H-NMR (DMSO-d 6 )6: 2.33 (3H, s), 3.69 (2H, s), 6.46 (1H, s), 15 6.58-6.59 (1H, m), 7.57-7.62 (1H, m), 7.66-7.70 (2H, m), 7.83 7.88 (2H, m), 8.15 (1H, d, J=8.3 Hz), 8.52 (1H, d, J=1.9 Hz), 8.57 (1H, d, J=2.3 Hz), 8.60-8.61 (1H, m), 8.86 (1H, d, J=4.9 Hz), 9.18 (1H, d, J=2.3 Hz), 2H not detected. Example 79 20 1-{5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-3 yl)sulfonyll-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride By a similar operation as in Example 24 and using tert butyl ({5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-3 yl)sulfonyl]-lH-pyrrol-3-yl)methyl)methylcarbamate (289 mg), 25 the title compound was obtained as colorless crystals (yield 74.2 mg, 29%). 1 H-NMR (DMSO-d 6 )S: 2.52 (3H, s), 3.94 (3H, s), 3.99 (2H, s), 6.65 (1H, d, J=1.8 Hz), 6.99-7.02 (1H, m), 7.42-7.47 (1H, m), 7.73-7.80 (2H, m), 7.84 (1H, d, J=1.8 Hz), 8.27-8.28 (1H, m), 3o 8.34-8.36 (1H, m), 9.10 (2H, brs). Example 80 (2-fluoro-3-{4-[(methylamino)methyll-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-2-yl}phenyl)methanol funarate By a similar operation as in Example 70 and using tert 35 butyl ({5-[2-fluoro-3-(hydroxymethyl)phenyll-1-(pyridin-3 211 ylsulfonyl)-lH-pyrrol-3-yl}methyl)methylcarbamate (238 mg), the title compound was obtained as colorless crystals (yield 55.3 mg, 22%). 1 H-NMR (DMSO-d6)5: 2.40 (3H, s), 3.80 (2H, s), 4.49 (2H, s), 5 6.43 (1H, d, J=1.8 Hz), 6.47 (2H, s), 6.97-7.02 (1H, m), 7.17 7.22 (1H, m), 7.54-7.62 (2H, m), 7.68 (1H, d, J=1.2 Hz), 7.84 7.88 (1H, m), 8.56 (iH, d, J=2.1 Hz), 8.86-8.88 (1H, m), 4H not detected. Example 81 10 1-(2-fluoro-3-{4-[(methylamino)methyl]-l-(pyridin-3 ylsulfonyl)-1H-pyrrol-2-yl}phenyl)ethanol fumarate By a similar operation as in Example 70 and using tert butyl ({5-[2-fluoro-3-(1-hydroxyethyl)phenyll-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate (318 mg), 15 the title compound was obtained as colorless crystals (yield 69.7 mg, 21%). 'H-NMR (DMSO-d6)S: 1.31 (3H, d, J=6.3 Hz), 2.40 (3H, s), 3.81 (2H, s), 4.90 (1H, q, J=6.3 Hz), 6.43 (1H, d, J=1.8 Hz), 6.47 (2H, s), 6.94-7.00 (1H, m), 7.16-7.22 (1H, m), 7.58-7.68 (3H, 20 m), 7.84-7.87 (1H, m), 8.55 (1H, d, J=2.7 Hz), 8.86-8.88 (1H, m), 4H not detected. Example 82 1-[5-(2-fluoro-3-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-iH pyrrol-3-yl]-N-methylmethananine fumarate 25 tert-Butyl {[5-(2-fluoro-3-methoxyphenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (475 mg) was dissolved in methanol (20 mL), a 4 mol/L hydrogen chloride ethyl acetate solution (2 mL) was added and the mixture was stirred at 700C for 20 min. The reaction mixture was 30 concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved 35 in ethanol (13 mL), fumaric acid (116 mg) was added, and the 212 obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 310 mg, 63%). 1 H-NMR (DMSO-d 6 )8: 2.41 (3H, s), 3.82 (2H, s), 3.86 (3H, s), 6.45 (1H, d, J=1.7 Hz), 6.48 (2H, s), 6.58-6.63 (1H, m), 7.10 5 7.16 (1H, m), 7.24-7.30 (1H, m), 7.59-7.63 (1H, m), 7.70 (1H, d, J=1.5 Hz), 7.86-7.90 (1H, m), 8.58 (1H, dd, J=2.3, 0.7 Hz), 8.87-8.89 (1H, m), 3H not detected. Example 83 1-[5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H 10 pyrrol-3-yl]-N-methylmethanamine fumarate tert-Butyl {[5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg) was dissolved in methanol (20 mL), a 4 mol/L hydrogen chloride ethyl acetate solution (2 mL) was added and the mixture was 15 stirred at 70 0 C for 20 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous 20 magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (6 mL), fumaric acid (49 mg) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 53 mg, 51%). 25 'H-NMR (DMSO-d 6 )S: 2.45 (3H, s), 3.44 (3H, s), 3.83 (2H, s), 6.36 (1H, d, J=1.5 Hz), 6.48 (2H, s), 6.79-6.86 (2H, m), 7.44 7.52 (1H, m), 7.60-7.65 (1H, m), 7.70 (1H, d, J=1.5 Hz), 7.88 7.92 (1H, m), 8.56 (1H, d, J=1.9 Hz), 8.88 (1H, dd, J=4.7, 1.7 Hz), 3H not detected. 30 Example 84 1-{5-[4-(difluoromethoxy)phenyl]-1-(pyridin-3-ylsulfonyl)-1H pyrrol-3-yl}-N-methylmethanamine fumarate By a similar operation as in Example 70 and using tert butyl ({5-[4-(difluoromethoxy)phenyl]-1-(pyridin-3 35 ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate (550 mg), 213 the title compound was obtained as colorless crystals (yield 313 mg, 62% for 2 steps). 'H-NMR (DMSO-d 6 )S: 2.38 (3H, s), 3.78 (2H, s), 6.40 (1H, s), 6.47 (2H, s), 7.15-7.24 (4H, m), 7.32 (1H, t, J=73.5 Hz), 5 7.54-7.58 (1H, m), 7.62 (1H, s), 7.77-7.80 (1H, m), 8.50 (1H, d, J=2.4 Hz), 8.84 (1H, d, J=4.5 Hz), 3H not detected. Example 85 N-methyl-1- [5- (4-methylpyridin-3-yl) -1- (pyridin-3-ylsulfonyl) 1H-pyrrol-3-yljmethanamine fumarate l0 tert-Butyl methyl{[5-(4-methylpyridin-3-yl)-1-(pyridin-3 ylsulfonyl)-lH-pyrrol-3-yl]methyl}carbamate (230 mg) was dissolved in methanol (20 mL), a 4 mol/L hydrogen chloride ethyl acetate solution (2 mL) was added and the mixture was stirred at 700C for 20 min. The reaction mixture was 15 concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 20 The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol (99:1->95:5) to give a free salt of the title compound. This was dissolved in ethyl acetate (8 mL), a solution of fumaric acid (90 mg) in methanol (2 mL) was added, and the obtained crystals were 25 collected by filtration to give the title compound as colorless crystals (yield 115 mg, 48%). 'H-NMR (DMSO-d,)5: 1.89 (3H, s), 2.43 (3H, s), 3.84 (2H, s), 6.45 (1H, d, J=1.9 Hz), 6.48 (2H, s), 7.29 (1H, d, J=4.9 Hz), 7.60-7.65 (1H, m), 7.73 (1H, d, J=1.9 Hz), 7.81-7.85 (1H, m), 30 7.98 (1H, s), 8.47 (1H, d, J=4.9 Hz), 8.51 (1H, d, J=1.9 Hz), 8.90 (1H, dd, J=4.9, 1.5 Hz), 3H not detected. Example 86 N-methyl-1- [5- (2-methylpyridin-3-yl) -1- (pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl]methanamine fumarate 35 By a similar operation as in Example 70 and using tert 214 butyl methyl{ [5-(2-methylpyridin-3-yl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yllmethyl}carbamate (278 mg), the title compound was obtained as colorless crystals (yield 93 mg, 32%). 5 'H-NNR (DMSO-d,)6: 2.00 (3H, s), 2.43 (3H, s), 3.83 (2H, s), 6.42 (1H, s), 6.47 (2H, s), 7.20-7.24 (1:H, m), 7.28-7.31 (1H, m), 7.59-7.63 (1H, m), 7.70 (1H, s), 7.80-7.84 (1H, m), 8.49 8.51 (2H, m), 8.88-8.90 (1H, m), 3H not detected. Example 87 10 1-{5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3 yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine 0.5 fumarate To absolution of tert-butyl ({5-(2-fluoropyridin-3-yl)-1 [(6-methylpyridin-3-yl)sulfonyll-1H-pyrrol-3 yl}methyl)methylcarbamate (86 mg) in ethanol (2 mL) was added 15 a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) at room temperature. The mixture was stirred for 2 hr, and concentrated under reduced pressure. The residue was basified with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract 20 was washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a free salt of the title compound as a pale yellow oil. The obtained free salt was dissolved in ethyl 25 acetate (2 mL) and added to a solution (2 mL) of fumaric acid (11.3 mg) in ethanol, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 14 mg, 18%). 30 'H-NMR (DMSO-ds)5: 2.33 (3H, s), 2.56 (3H, s), 3.68 (2H, s), 6.44 (1H, s), 6.53 (1H, s), 7.41-7.50 (2H, m), 7.64 (1H, s), 7.74-7.81 (2H, m), 8.34 (1H, s), 8.48 (1H, s), 2H not detected. Example 88 35 1-[4-chloro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl) 215 1H-pyrrol-3-yl]-N-methylmethanamine fumarate 4-Chloro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3 ylsulfonyl)-lH-pyrrole-3-carbaldehyde (320 mg) was dissolved in a solution of methylamine hydrochloride (591 mg) in 5 methanol (32 mL) and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (557 mg) was added and the mixture was stirred for 3 hrs. The reaction mixture was concentrated under reduced pressure at 300C, a saturated aqueous sodium hydrogencarbonate solution was added to the 1o residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=99:1-->95:5) to 1,5 give a free salt of the title compound. This was dissolved in ethyl acetate (8 mL), a solution of fumaric acid (102 mg) in methanol (2 mL) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 52 mg, 12%). 20 1 H-NMR (DMSO-d6)8: 2.39 (3H, s), 3.70 (2H, s), 6.65 (2H, s), 7.48-7.53 (1H, m), 7.63-7.68 (1H, m), 7.81 (1H, s), 7.84-7.96 (2H, m), 8.40-8.42 (1H, m), 8.65 (1H, d, J=1.9 Hz), 8.93 (1H, dd, J=4.9, 1.5 Hz), 3H not detected. Example 89 25 N-methyl-l-[1-(pyridin-3-ylsulfonyl)-5-(2-thienyl)-1H-pyrrol 3-yl]methanamine fumarate By a similar operation as in Example 70 and using tert butyl methyl{[l-(pyridin-3-ylsulfonyl)-5-(2-thienyl)-lH pyrrol-3-yllmethyl}carbamate (315 mg), the title compound was 30 obtained as colorless crystals (yield 165 mg, 51%). 'H-NMR (DMSO-d 6 )S: 2.43 (3H, s), 3.83 (2H, s), 6.47 (2H, s), 6.52 (1H, d, J=1.8 Hz), 7.07-7.12 (2H, m), 7.55-7.62 (2H, m), 7.70 (1H, d, J=1.8 Hz), 7.84-7.88 (1H, m), 8.53-8.54 (1H, m), 8.83-8.85 (1H, m), 3H not detected. 35 Example 90 216 N-methyl-1- [5- (3-methylpyridin-2-yl) -1- (pyridin-3-ylsulfonyl) 1H-pyrrol-3-yl methanamine fumarate By a similar operation as in Example 70 and using tert butyl methyl{[5-(3-methylpyridin-2-yl)-1-(pyridin-3 5 ylsulfonyl)-lH-pyrrol-3-yllmethyl}carbamate (229 mg), the title compound was obtained as colorless crystals (yield 124 mg, 53%). 'H-NMR (DMSO-d 6 )5: 2.18 (3H, s), 2.44 (3H, s), 3.86 (2H, s), 6.46 (2H, s), 6.52 (1H, d, J=1.8 Hz), 7.32-7.36 (1H, m), 7.66 10 7.74 (3H, m), 8.17-8.21 (1H, m), 8.28-8.30 (1H, m), 8.87-8.90 (2H, m), 3H not detected. Example 91 2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-2-yl}benzonitrile fumarate 15 By a similar operation as in Example 70 and using tert butyl {[5-(3-cyano-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-yllmethyl}methylcarbamate (170 mg), the title compound was obtained as colorless crystals (yield 96 mg, 74%). 20 1 H-NMR (DMSO-d 6 )S: 2.39 (3H, s), 3.80 (2H', s), 6.47 (2H, s), 6.59 (1H, d, J=1.5 Hz), 7.43-7.48 (1H, m), 7.52-7.57 (1H, m), 7.60-7.65 (1H, m), 7.76 (1H, d, J=1.8 Hz), 7.89-7.93 (1H, m), 8.02-8.07 (1H, m), 8.59-8.60 (1H, m), 8.89-8.91 (1H, m), 3H not detected. 25 Example 92 4-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-lH-pyrrol 2-yl}thiophene-3-carbonitrile fumarate By a similar operation as in Example 70 and using tert butyl {[5-(4-cyano-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H 30 pyrrol-3-yl]methyl}methylcarbamate (297 mg), the title compound was obtained as colorless crystals (yield 155 mg, 50%). 'H-NMR (DMSO-d6)5: 2.41 (3H, s), 3.84 (2H, s), 6.47 (2H, s), 6.56 (1H, d, J=2.1 Hz), 7.59-7.74 (1H, m), 7.67 (1H, d, J=3.0 35 Hz), 7.73-7.74 (1H, m), 7.86-7.90 (1H, m), 8.57-8.59 (2H, m), 217 8.87-8.89 (1H, m), 3H not detected. The structures of the compounds described in Reference Examples are shown in Tables 1-14. 5 10 15 20 25 30 35 218 Table 1 R2 R5a N Ria Ref. Ex. No. Rla R2a R 3 a R4a R5a 6 H H CO 2 Et CI 7 H H CO 2 Et CI 8 H Me CO 2 Me CI 9 H H CO 2 Et H 10 H H CO 2 Et H 11 H Me CO 2 Me H 12 H H CO 2 Et H 13 H H CH 2 OH H F 14 H Me CH 2 OH H 15 H H CHO H 16 H Me CHO H F 17 H H CHO H
CF
3 18 H / H CHO H 19 H H H CO 2 Me H 20 H H Me CO 2 Me H 21 H H H CO 2 Et Me 22 H Br H CO 2 Me H 219 Table 2 R3Sa 4 a Ri8 Ref. Ex. No. Ria R2a R3a R4a Rsa 23 H Br Me CO 2 Me H 24 H Br H CO 2 Et Me 36 C 302 H CO 2 Et H 37 Me 802 H CO 2 Et H N 38 H 2 N 8/0S 2 H CO 2 Et H 39 / 02 H CO 2 Et H 40 C 2 O - H CO 2 Et H 41 Q-S' 2 Br H CO 2 Me H 42 O ~-s' 2 Br Me CO 2 Me H 43 Q'-S2 H H CO 2 Et Me 44 -dSO2 Br H CO 2 Et Me H CO 2 Et Me 46 SO2 Br H CH 2 OH H 47 87- 02 H H CH 2 OH Me 48 &-S/2 Br H CHO H 49 (Ds/ 2 Br Me CHO H 50 H 0 - Me CHO H 220 Table 3 R 1 4 a R2a ; R5a 1 a Ref. Ex. No. Rla R2a R 3 a R 4 a Rsa 51 802 H H CHO Me 52 H H H CHO Me 53 H H CHO Me 54 SO2 Br H CHO Me / H CHO H 56 MeO 2 H CHO H 57 , N 2 H CHO H CI 58 /2 H CHO H N >S0 2 H CHO H 60 c1 -SO/2 H CHO H Me 61 H CHO Me 62 Me SO 2 H CHO H N 63 0j 2 H CHO H
CF
3 64 j 1 2 cQH CHO H 65- Me CHO H 66 C)-SO2 Me CHO H 221 Table 4 Ra R 4 a Rla Ref. Ex. No. R 1 a R 2 . R 3 a R 4 a R 5 a 67 MeyN 2 Me CHO H Me' / 68 so 2 Me CHO H Me Me 69 SO 2 Me CHO H Me F 70 dS 2 Me CHO H 71 O -ZO 2 Br H CH 2 NHMe H 72 O SO 2 Br H CH 2 NC H 'Boo 73 H Br H CH 2 NZ oe H "Boo 74 so 2 Br H CH 2 NM H CI 75 2 H CH 2 NM H t - 2 2 Boo 76 CI / 02 H CH2N( M H Me 77 ci Z02 H CH2N o H / BoMe 78 Me- -S0 2 H CH 2 N" oe H "Boo _02 2NMe 79 s 2 H CH 2 N "o H 80 - F H CH 2 N" oe H 2Boo 222 Table 5 R2a R5a R la Ref. Ex. No. Rla R2. R 3 a R4a R6a Me 81 SH CH2N "I H 82 (0 4 2 F BH CH2N oc H 82 , M H CH2N Me H N3 H CH2N Me H -42 CH/N...Bo H NC 84 so2 H CH2N'Me H 85 4 F H CH2N Me H F 86 H F H CH2N% M H F 88 H CI H CH2NB M H FF 89 S2 F H CH2M H 90 2 H CH2Me H F 91 2 H CH2N Me H Me 93 Br H CH2NC Me 223 Table 6 R ~ 4 a Rla Ref. Ex. No. Rla R 2 a R 3 a R 4 a Rsa F 97 H H CO 2 Et CI F 98 H H CO 2 Me CI 99 H F CO 2 Me CI 100 H H CO 2 Et H F 101 H H CO 2 Me H 102 H F CH 2 Me H F 103 H H CH 2 OH H 104 H H CH 2 OH H F 105 H H CHO H F 106 H 0 - - H CHO H 107 H H H CHO H 111 H F H H 112 H Br H CHO H 224 Table 7 Ra R 4 a Ria Ref. Ex. No. Rla R 2 a R 3 a R4 Rea 113 H H CHO H 114 H CI CHO H F 115 H F CHO H 116 H F CHO H 122 / SO 2 H CO 2 Et H B r 123 / , 2 H CO 2 Et H FsC Me 124 so 2 H CO 2 Et H 15 N--2 F CO 2 Me H 126 B 0 2 H CHO H Br 127 / H CHO H
F
3 C Me 128 -s 2 H CHO H 225 Table 8 R 3J 4 a Ref. Ex No. Rla R 2 a R 3 a R 4 R 129 r/-S02 F CHO H 130 H CHO H F 131 DS'2 (~ ~~-- H CHO H 132 ci~~s~2 ~H CHO H F 133 Me- 4 2 H CHO H 134 cn ~' 2 H CHO H 135 Nl^ / 0 H CHO H Me 136 O 2 H CHO H 137 CIO CHO H 138 ~ - 2 /F CHO H 226 Table 9 R 4a Rla Ref. Ex. No. R 1 a R2a R 3 a R 4 a R5a 139 -02 F CHO H 140 S& H CHO CI F F 141 H CHO CI N-O/ d 1 44 H CH2NC c H Bre 143 B S Me H CH 2 N"Mc H CHO 144 /-S02 H CH2N. c H 145 0 -S0 2 MeO 2 S / H CH2N Me H
CH
2 OH 146 /S 2 H CH2N oc H 227 Table 10
R
3 a
R
4 a R2a R 5a Ref. Ex. No. Rla R2a R 3 a R4a Ra Me 147 H Me H CHO H Me SMe 148 H H CHO H Br 149 H H CHO H SOMe 150 H H CHO H
SO
2 Me 151 H H CHO H 152 H i/CHO H 153 3S.
2 Me H CHO H Me SMe 154 H CHO H Br 155 S02 6 H CHO H
SO
2 Me 156 So 2 H CHO H CN 157 /S/2 H CHO H 228 Table 11 R 3 , 4 a Ria Ref. Ex. No. RaR 2 a R 3 a aRa F 158 I'/0 CHO H 159 4~. 2 ~ /H CHO H Me 160 0/S'o 2 /H CHO Br F 161 ~~~ 2 /CN CHO H 162 0 - //0 H CHO CN 163 MeO-'j' 2 Br H CH2N ' M H 164 O Z2NC / - H CH2N. Me H F 165 4jO2 /H CH2N...Me H NC F 166 2ss H CH 2 N*' Me H "Boo MeO 167 4js 2 /H CH2N'.. H 229 Table 12 R~a
R
4 a Ref. Ex. No. RIa R 2 a R 3 a R 4 a 2 e 0-- F 168 (- Q/H CH 2 N..Me H F 19H CH 2 N M H F 170 6 - 2 H CH2..Me H 171 0 ,/b H C2*.M 172 CI 17 -S/o CI- H CH 2 N"Me H 173 0 -8 2 BoHoHN M F / Hx zo"o
HO
175 (jS 2 /H CH 2 N. Me H Me
HO
176 /02 H CH2N*'Boo H Me 177 /s 2 H CH2NK.Me H 178 N H CH 2 NC M H OMe 230 Table 13 Raa R4a R 2a Rsa Ref. Ex. No. R 1 a R2a R 3 a R4a Rsa 180 F H CH 2
N(
8 e H F e 181 F H CH 2 NM H Me 183 / so 2 H CH2N" Me H 187 Me / 0 2 Br H CH2NC Me H F 188 Me / 0 2 H CH2N oe H F 189 / - H CHO H F 190 H / H CHO H 191 H / CI CHO H 192 CI CHO H H CH2NB H Me 196 j 02 H CH 2 N Me H 231 Table 14 Raa R 4 * R a R a R 5a Ref. Ex. No. Rla R2a R3a R 4 Rea HO 197 / 2 H CH2N Boo H N F 198 2 N H CH2N C oc H 199 2 Br H CH 2 N.. oe H 200 N 2 H CHNMe H The structures of the compounds described in Examples are 5 shown in Tables 15-23. 232 Table 15 R3 Me H
R
2 b
R
4 b Rib Ex. No. Rib R2b Rab ROb addition salt 1 802 H H 2HCI 2 MeO 0/ O 2 H H HCI 3 MeHN SO02 H H 2HCI NHMe 4 2 H H 2HCI 5 MeH N / 2 H H HCI 6 O 0 2 H Me 2HCI 7 Me < H H 2HCI 8 802 H H HOOC
CF
3 COOH 9 S2 H H 2HCI 10S'2 Me H 2HCI 1 J 2 Me H HCI Me C / 12 M*'/ s0 2 Me H 2HCl Me/ cl 13 MeN S02 Me H HCI Me 14 Me k / Me H HCI Me 233 Table 16 Rw Me 2 R/ 4b Rib Ex. No. Rib R 2 b Rab R4b addition salt Me 15 M
SO
2 Me H
CF
3 COOH 16 2 Me H HCI 0I 17 SO2 H H HCI 18 H 2 N-</ S0 2 H H 19 2-/SO 2 O -H H 2HCI 202 O H H HOOC Me
SO
2 H H OO COOH N- / /=OOI 21 HO / 0 2 H H HC 21 42COOM Me 22 O s/ o H MCI 23 NC- / O 2 O H H HCI 24 Me / 02 H H 2HCI 25 c -SO2 z H H HCI 26 O~ SO2 F H H 2HCI 27 N-S 2 6 H H 2HCI Me 28 0 2 F H H 2HCI 234 Table 17 RMe
R
2 b R 4 b RIb Ex. No. Rib - 2b Rab R 4 b addition salt 29 H H 2HCI 2 N 30 H H HCI 31 0H H 2HCI F 32F H H 2HCI F 33 2H H HCI FF 34 2 CI - H H 2HCI 35 2H H HCI 36 0 -02 H Me HOOC COOH 235 Table 18 Rs Me R2b R4b Rib Ex. No. Rib R2b R 3 b R 4 b addition salt 37 2H H HCI
F
3 C e 38 2 H H 2HCI 39H H
HO
2 O 40 ~ - 2 H H 2HCI 41 t -SO 2 F H 2HCI 42 O 2 9F H F H 0.5 H02 2 H 44 Me /02 H H 2HCI 45 2 1H H HCI F 46 Me 02 H H HO2 CO2H C0 2 H HO 47 S2 H H H
CO
2 H 236 Table 19 R R Me
R
4 b Ex. No. Rib R 2 b R 3 b R4b addition salt F 48 / 02 Cl H HO 2
CO
2 H F 49
S/O
2 F H HO 2
CO
2 H 50 4 F H H2 CO 2 H 51 2 H CI HO 2 CO2H F 52 z 2 H Cl H02 CO 2 H 53 B SO 2 H H HCI 54 NC SO0 2 H H HCI NC 55 2 H H HCI MeO 2 C 56 M / 802 H H 2HCI M e Me 57 -S/O 2 Me / H H HCI 237 Table 20 R3 Me H
R
2 b R 4 b RIb Ex. No. Rib R 2 b R 3 b Rab addition salt 58 02 MeO 2 S / H H 2HCI
CH
2 OH 59N SO 2 H H H 2 59 -S02 6 CO-c 2 H e 60 H H HO 2 O -jSO2 02H
CO
2 H 238 Table 21 R 4 Ex. No. R10 R 2 0 R 3 c R 4 c R 5 4 addition salt
HO
2 61 O -8O 2 H CH 2 NHMe H CO2H Me HO 2 62
SO
2 Me H CH 2 NHMe H HO2 0 2 H Me SMe 63 -0 2 ( / H CH 2 NHMe H H02 CO2H ,90,Me H02 H 64 2 ~H
CH
2 NHMe H 0.HO 2 C2H 66 4O2 H CH2NHMe H H02 HO 2 66 (Q/ SO 2 H CH 2 NHMe H CO2H Me SOMe 67 0 -sO 2 H CH 2 NHMe H HO2 CO2H 68 C 04 CN CH2NHMe H HO2 CO 2 H 69 02 H CH2NHMe CN HO2 CO 2H 70 -S02 NCH CH2NHMe H H02 " CO2H
HO
2 71 8f 02 N H CH 2 NHMe H 0.5 3C9 2 H
NC
2 2HO 2 Table 22
R
2 or ; R 5 c R14 Ex. No. Rio R 2 c R 3 4 R 4 R 5 O addition salt
HO
2 72 -SO2 H CH 2 NHMe H H C2H MeO Me
HO
2 , 73
SO
2 H CH 2 NHMe H
CO
2 H H0 2 742 H CH 2 NHMe H F 75 2 / H CH 2 NHMe H HO2 CO 2 H 76 H CH 2 NHMe H HO 2
CO
2 H SH CH HO 2 C2H 77 O -SO2 Cl H CH 2 NHMe H 1.5 CO 2 H H0 2 78 MejO S2CI H CH 2 NHMe H 0.5 C 79 MeO / SO 2 H CH 2 NHMe H HCI 80 H CH 2 NHMe H
CO
2 H e 81 HO-SO -/ H CH 2 NHMe H H2C-C2 MeO FH0 82 H CH 2 NHMe H 240 Table 23 R 2c R54 R4o Ex. No. RiC R 2 c R 3 c R4 R54 addition salt 83
SO
2 H CH 2 NHMe H H C2H Me 84 2 F H CH 2 NHMe H H02 CO 2 H F Me
H
2 85 ~ SO2 / H CH 2 NHMe H H2 C2 86 zo2 H CH2NHMe H HO2 CO2H N0
CO
2 H 87 Me -0 2 H CH 2 NHMe H 0.H C0 2 H 88 32 C1 CH 2 NHMe H H2 e2 C O 2 H 89 ( 02 H CH 2 NHMe H H02 CO2H e 90 H CH 2 NHMe H H02 N C0 2 H 91 - 0 2 / H CH 2 NHMe H H2 CO2H N
SHO
2 92 j=--S/ 2 s/H H 2 NHMe H C0 2 H 241 Experimental Example 1 Proton potassium - adenosine triphosphatase (H+,K+-ATPase) inhibitory activity test According to the method [Biochim. Biophys. Acta, 728, 31 5 (1983)] of Wallmark et al., a gastric mucous membrane microsomal fraction was prepared from the stomach of swine. First, the stomach was removed, washed with tap water, immersed in 3 mol/L brine, and the surface of the mucous membrane was wiped with a paper towel. The gastric mucous lo membrane was detached, chopped, and homogenized in a 0.25 mol/L saccharose solution (pH 6.8) containing 1 mmol/L EDTA and 10 mmol/L tris-hydrochloric acid using polytron (Kinematica) . The obtained homogenate was centrifuged at 20,000xg for 30 min and the supernatant was centrifuged at 15 100,00Oxg for 90 min. The precipitate was suspended in 0.25 mol/L saccharose solution, superimposed on a 0.25 mol/L saccharose solution containing 7.5% Ficoll, and centrifuged at 100,000xg for 5 hr. The fraction containing the interface between the both layers was recovered, and centrifugally 20 washed with 0.25 mol/L saccharose solution. The obtained microsomal fraction was used as a proton, potassium - adenosine triphosphatase standard product. To 40 L of a 50 mmol/L HEPES-tris buffer (5 mmol/L magnesium chloride, 10 mmol/L potassium chloride, 10 pmol/L 25 valinomycin, pH=6.5) containing 2.5 gg/mL (based on the protein concentration) of the enzyme standard product was added a test compound (5 gL) dissolved in a 10% aqueous dimethyl sulfoxide solution, and the mixture was incubated at 370C for 30 min. The enzyme reaction was started by adding 5 pL of a 2 mmol/L 30 adenosine triphosphate tris salt solution (50 mmol/L HEPES tris buffer (5 mmol/L magnesium chloride, pH 6.5)). The enzyme reaction was carried out at 370C for 20 min, and 15 gL of a malachite green solution (0.12% malachite green solution in sulfuric acid (2.5 mol/L), 7.5% ammonium molybdate and 11% 35 Tween 20 were mixed at a ratio of 100:25:2) was added to 242 quench the reaction. After allowing to stand at room temperature for 15 min, the resulting reaction product of inorganic phosphorus with malachite green was colorimetrically determined at a wavelength of 610 nm. In addition, the amount 5 of the inorganic phosphoric acid in the reaction solution free of potassium chloride was measured in the same manner, which was subtracted from the inorganic phosphoric acid amount in the presence of potassium chloride to determine the proton, potassium - adenosine triphosphatase activity. The inhibitory 10 rate (%) was determined from the activity value of the control and the activity values of various concentrations of the test compound, and the 50% inhibitory concentration (IC 50 ) of the proton, potassium - adenosine triphosphatase was determined. The results are shown in Table 24. 15 Experimental Example 2 Human liver cancer-derived cell line HepG2 (ATCC No. HB 8065) was passaged using Dulbecco's Modified Eagle medium (DMEM; Invitrogen) containing 10% fetal bovine serum (FBS; TRACE SCIENTIFIC LTD.), 1 mmol/L sodium pyruvate (Invitrogen), 20 2 mmol/L L-glutamine (Invitrogen), 50 IU/mL penicillin (Invitrogen) and 50 gg/mL streptomycin (Invitrogen) at 5% C02, 370C. The test reagent was prepared with DMSO to 10 mM, and further diluted with DMEM medium containing 0.5% FBS, 1 mmol/L sodium pyruvate, 2 mmol/L L-glutamine, 50 IU/mL penicillin and 25 50 g/mL streptomycin to a final concentration of DMSO of 0.1%. HepG2 (2x104 cells/well) was cultured on a 96 well white plate (Costar) with the test reagent at 5% C0 2 , 370C. After culture for one day, the intracellular ATP content was measured using ATPLitem (PerkinElmer Life Sciences) . The results are shown in 30 Table 24 (n>3, average value ± SD) as a relative value (%) to control (without addition of drug) at 30 pm. 35 243 Table 24 Example No. H+/K+-ATPase inhibitory ATP content (%, 30 p$) activity (IC50, nM) 2 13 45.2 5 65 73.9 7 34 76.5 8 22 87.9 29 41 71.5 32 8.9 53.6 41 43 86.7 44 48 78.5 47 58 81.8 74 210 95.2 From the results of Table 24, it is clear that compound (I) of the present invention has a superior H+/K-ATPase 5 inhibitory activity, and further shows low cytotoxicity. Industrial Applicability Since compound (I) of the present invention shows a superior proton pump inhibitory effect (while conventional proton pump inhibitors such as omeprazole, lansoprazole etc. 10 form a covalent bond with a cysteine residue of H+/K+-ATPase and irreversibly inhibit the enzyme activity, since compound (I) inhibits the proton pump (H+/K+-ATPase) activity reversibly and in a K+ antagonist inhibitory manner to consequently suppress acid secretion, it is sometimes referred 15 to as a potassium-competitive acid blocker: P-CAB or an acid pump antagonist (ACPA or APA)), it can provide a clinically useful pharmaceutical composition for the prophylaxis and/or treatment of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, 20 symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper 244 gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress. Since compound (I) shows low toxicity and is superior in water solubility, in vivo kinetics and efficacy expression, it is 5 useful as a pharmaceutical composition. Moreover, since compound (I) is stable even under acidic conditions, which enables oral administration of the compound as a conventional tablet and the like without formulating an enteric-coated preparation. This has a consequence that the preparation of lo tablet and the like can be made smaller, which is advantageous in that it is easily swallowed by patients having difficulty in swallowing, particularly the elderly and children. In addition, since a sustained release effect afforded by enteric-coated preparations is absent, expression of a gastric 15 acid secretion-suppressive action is rapid, and alleviation of symptoms such as pain and the like is rapid. This application is based on patent application Nos. 2005-250356 and 2006-100626 filed in Japan, the contents of which are incorporated in full herein by this reference. 245

权利要求:
Claims (17)
[1] 1. A compound represented by the formula (I): 3 H2 /R R C--N R 2) N R 4 H () I 02 R 1 wherein R1 is a monocyclic nitrogen-containing heterocyclic 5 group optionally condensed with a benzene ring or a heterocycle, the monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent (s), R 2 is an optionally substituted C 6 - 14 aryl group, an optionally substituted thienyl lo group or an optionally substituted pyridyl group, R 3 and R 4 are each a hydrogen atom, or one of R 3 and R4 is a hydrogen atom and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and R5 is an alkyl group, or a salt thereof. 15
[2] 2. A compound represented by the formula (I): 3 H2 /R R C--N I H 22 R1 wherein R1 is a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a 20 heterocycle, the monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s), R2 is an optionally substituted C 6 .- 14 aryl group or an optionally substituted thienyl group, R3 and R4 are each a hydrogen atom, or one of R3 25 and-R 4 is a hydrogen atom and the other is an optionally 246 substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and R5 is an alkyl group, or a salt thereof. 5 3. The compound of claim 1 or 2, wherein R1 is a monocyclic nitrogen-containing heterocyclic group.
[3] 4. The compound of claim 1 or 2, wherein the monocyclic nitrogen-containing heterocyclic group is a pyridyl group. 10
[4] 5. The compound of claim 1 or 2, wherein R 2 is a phenyl group optionally substituted by 1 to 5 substituents selected from (i) a halogen atom and (ii) a C 1 - 6 alkyl optionally substituted by 1 to 5 halogen atoms. 15
[5] 6. The compound of claim 1 or 2, wherein R 2 is a pyridyl group optionally substituted by 1 to 4 substituent(s) selected from Cj.e alkyl, a halogen atom, alkoxy, cyano, acyl, nitro and amino. 20
[6] 7. The compound of claim 1 or 2, wherein R 3 and R 4 are each a hydrogen atom.
[7] 8. The compound of claim 1 or 2, wherein R 5 is a methyl group. 25
[8] 9. 1-{5-(2-Fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl] 1H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof.
[9] 10. 1-[4-Fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3 30 yl]-N-methylmethanamine or a salt thereof.
[10] 11. N-Methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yllmethanamine or a salt thereof. 35 12. 1-[5-(2-Fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H 247 pyrrol-3-yl]-N-methylmethanmine or a salt thereof.
[11] 13.1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol-3 yl]-N-methylmethanamine or a salt thereof. 5
[12] 14. N-Methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl) 1H-pyrrol-3-ylmethanamine or a salt thereof.
[13] 15. A prodrug of the compound of claim 1 or 2. 10
[14] 16. A pharmaceutical composition comprising the compound of claim 1 or 2 or a prodrug thereof.
[15] 17. The pharmaceutical composition of claim 16, which is an 1.5 acid secretion inhibitor.
[16] 18. The pharmaceutical composition of claim 16, which is a potassium-competitive acid blocker. 20 19. The pharmaceutical composition of claim 16, which is an agent for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric 25 cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress. 30 20. A method of treating or preventing peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (Symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or a 35 method of inhibiting upper gastrointestinal hemorrhage due to 248 peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress, which comprises administering an effective amount of the compound of claim 1 or 2 or a prodrug thereof to a mammal.
[17] 21. Use of the compound of claim 1 or 2 or a prodrug thereof for the production of a pharmaceutical composition for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, 10 symptomatic gastroesophageal reflux disease (Symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress. 15 249

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同族专利:

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公开号 | 公开日

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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CA2582777A1|2004-09-30|2006-04-06|Takeda Pharmaceutical Company Limited|Proton pump inhibitors|

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法律状态:
2016-04-21| DA2| Applications for amendment section 104|Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 19 FEB 2016 . |

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2016-07-07| DA3| Amendments made section 104|Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 19 FEB |

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2016-07-14| FGA| Letters patent sealed or granted (standard patent)|

优先权:

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申请号 | 申请日 | 专利标题

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JP2005-250356||2005-08-30||

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JP2006-100626||2006-03-31||

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AU2006285641A|AU2006285641A1|2005-08-30|2006-08-29|1-heterocyclylsulfonyl, 2-aminomethyl, 5-aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors|

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AU2013200142A|AU2013200142C1|2005-08-30|2013-01-11|1-Heterocyclylsulfonyl, 3-aminomethyl, 5-aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors|AU2013200142A| AU2013200142C1|2005-08-30|2013-01-11|1-Heterocyclylsulfonyl, 3-aminomethyl, 5-aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors|

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AU2015268744A| AU2015268744B2|2005-08-30|2015-12-15|1-Heterocyclylsulfonyl, 3-aminomethyl, 5-aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors|