IL211335A

Pyrrole compounds

Abstract

This record has no abstract on file.

Term

No projected expiry on record.

9 claims: 1 independent, 8 dependent

1
4 1. A compound represented by the formula (I) 211335/3 CLAIMS wherein R2 is a halogen atom, a Ci-6 alkyl group optionally substituted by halogen or a Ci_6' alkoxy group optionally substituted by halogen, or a salt thereof.

437 paragraphs in 12 sections, as filed

PYRROLE COMPOUNDS TAKEDA PHARMACEUTICAL COMPANY LIMITED C:72614 WO 2010/024451 PCT/JP2009/065279

DESCRIPTION PYRROLE COMPOUNDS

TECHNICAL FIELD

[0001]

The present invention relates to pyrrole compounds having an acid secretion suppressive activity.

[0002] (BACKGROUND OF THE INVENTION)

Proton pump inhibitors represented by omeprazole, which io suppress gastric acid secretion for the treatment of peptic ulcer, reflux esophagitis and the like, have been widely used 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 is inhibitors are unstable under acidic conditions, they are often formulated as enteric preparations, in which case several hours are required before onset of action, and about 5 days to exhibit maximum efficacy by consecutive administration In addition, since the existing proton pump inhibitors show 20 variable treatment effects due to metabolic enzyme polymorphism and drug interaction with medicaments such as diazepam and the like, an improvement has been desired.

As pyrrole compounds having a proton pump inhibitory action, patent reference 1 describes a compound represented by 25 the formula: [0003] Γ

X

[0004] 1 WO 2010/024451 PCT/JP2009/065279 wherein X and Y are the same or different and each is a bond or a spacer having 1 to 20 atoms in the main chain, r1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, r2, r3 and r* are the same or 5 different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted thienyl group, an optionally substituted benzo[b]thienyl group, an optionally substituted furyl group, an optionally substituted pyridyl group, an optionally substituted pyrazolyl io group, an optionally substituted pyrimidinyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and r5 and r6 are the same or different and each is a hydrogen atom or an optionally substituted hydrocarbon group. In addition, as a pyrrole compound having a proton pump inhibitory activity, 15 patent document 2 describes a compound represented by the formula [0005]

[0006] 20 wherein r7 is a monocyclic nitrogen-containing heterocyclic group optionally fused with a benzene ring or heterocycle, the monocyclic nitrogen-containing heterocyclic group optionally fused with a benzene ring or heterocycle optionally has substituent(s), r8 is an optionally substituted Cg-n aryl group, 25 an optionally substituted thienyl group or an optionally substituted pyridyl group, r9 and r10 are the same or different and each is a hydrogen atom or one of r9 and r10 is a hydrogen atom and the other is an optionally substituted lower alkyl 2 WO 2010/024451 PCT/JP2009/065279 group, an acyl group, a halogen atom, a cyano group or a nitro group, and r11 is an alkyl group, and the like.

[0007]

Furthermore, as a therapeutic drug for neoplastic 5 diseases or autoimmune diseases, patent reference 3 describes a compound represented by the formula: [0008]

[0009] io wherein r7 is aryl, aralkyl, heteroaryl or the like, r9 is aryl, heteroaryl or the like, and r9 is aryl, heteroaryl, optionally substituted aminomethyl· or the like.

CITATION LIST PATENT LITERATURE is [0010]

Patent reference 1: WO 2006/036024 Patent reference 2: WO 2007/026916 Patent reference 3: WO 2004/103968 SUMMARY OF THE INVENTION 20 PROBLEMS TO BE SOLVED BY THE INVENTION [0011] A medicament that effectively suppresses gastric acid secretion as known proton pump inhibitors, which is improved in instability under acidic conditions, dispersion of effects 25 due to metabolic enzyme polymorphism and drug interaction, which are problems of known proton pump inhibitors, is expected to show more superior treatment effect on peptic ulcer, reflux esophagitis and the like. As the situation stands, however, a proton pump inhibitor capable of 3 WO 2010/024451 PCT/JP2009/065279 sufficiently satisfying these requirements has not been found. It is therefore an object of the present invention to provide a compound having a superior acid secretion suppressive effect (particularly, proton pump inhibitory effect), which has been 5 improved in these problems.

MEANS OF SOLVING THE PROBLEMS

[0012]

The present inventors have conducted various studies and found that a compound represented by the formula (I): io [0013]

Ν'

(I) [0014] wherein the symbols are to be defined below, or a salt thereof [hereinafter to be sometimes abbreviated as compound (I)] is unexpectedly has a very strong proton pump inhibitory effect, and is fully satisfactory as a medicament, which resulted in the completion of the present invention.

[0015]

Accordingly, the present invention relates to the so following.

[1] A compound represented by the formula (I) [0016]

(I)

[0017] 4 WO 2010/024451 PCT/JP2009/065279 wherein A is a pyridyl group having at least one substituent: [0018]

[0019] 5 wherein R1, R2 and R3 are each a hydrogen atom, a halogen atom, a Ci-6 alkyl group optionally substituted by halogen or a Ci-e alkoxy group optionally substituted by halogen, R4 and R6 are each a hydrogen atom, a halogen atom or a Ci-β alkyl group optionally substituted by halogen, R5 is a hydrogen atom, a io halogen atom, a Ci-s alkyl group optionally substituted by halogen or a Ci_6 alkoxy group optionally substituted by halogen, and R7 is a hydrogen atom or a Ci_g alkyl group optionally substituted by halogen, or a salt thereof, [2] the compound of the above-mentioned [1], wherein A is is represented by the formula (A—1) wherein R1 and R3 are both hydrogen atoms, R2 is a halogen atom, a Ci-e alkyl group optionally substituted by halogen or a Ci_6 alkoxy group optionally substituted by halogen, or a salt thereof, [3] the compound of the above-mentioned [2], wherein R2 is a Ci_ 20 $ alkyl group or a Ci-e alkoxy group, or a salt thereof, [4] l-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin- 2-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine, or a salt thereof, [5] l-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[{5-fluoropyridin- 25 2-yl)sulfonyl]-lH-pyrrol-3-yl]-N-methylmethanamine, or a salt thereof, [6] l-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin- 2-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine, or a salt thereof, 30 [7] l-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin- 5 WO 2010/024451 PCT/JP2009/065279 3-yl) sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine, or a salt thereof, [8] l-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin- 3-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine, or a salt 5 thereof, [9] a prodrug of the compound of the above-mentioned [1] or a salt thereof, [10] a pharmaceutical composition comprising the compound of the above-mentioned [1] or a salt thereof or a prodrug thereof, io [11] the pharmaceutical composition of the above-mentioned [10], which is an acid secretion inhibitor, [12] the pharmaceutical composition of the above-mentioned [10], which is a potassium-competitive acid blocker, [13] the pharmaceutical composition of the above-mentioned is [10], which is an agent for the prophylaxis or treatment of peptic ulcer, Zollinger-Ellison syndrome, gastritis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), Barrett's esophagus, functional dyspepsia, gastric cancer, stomach MALT lymphoma, or ulcer caused by non- 20 steroidal anti-inflammatory drug, gastric hyperacidity or ulcer due to postoperative stress; or an inhibitor of upper gastrointestinal bleeding due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress, [14] a method for treating or preventing peptic ulcer, 25 Zollinger-Ellison syndrome, gastritis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), Barrett's esophagus, functional dyspepsia, gastric cancer, stomach MALT lymphoma, or ulcer caused by non-steroidal antiinflammatory drug, gastric hyperacidity or ulcer due to 30 postoperative stress; or a method of inhibiting upper gastrointestinal bleeding due to 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 a salt thereof or a prodrug thereof 35 to a mammal, 6 WO 2010/024451 PCT/JP2009/065279 [15] use of the compound of the above-mentioned [1] or a salt thereof or a prodrug thereof for the production of an agent for the prophylaxis or treatment of peptic ulcer, Zollinger-Ellison syndrome, gastritis, reflux esophagitis, symptomatic 5 gastroesophageal reflux disease (symptomatic GERD), Barrett's esophagus, functional dyspepsia, gastric cancer, stomach MALT lymphoma, or ulcer caused by non-steroidal anti-inflammatory drug, gastric hyperacidity or ulcer due to postoperative stress; or an inhibitor of upper gastrointestinal bleeding due io to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress, and [16] the compound of the above-mentioned [1], wherein A is a pyridyl group having at least one substituent, the formula (A-1) or the formula (A—2) wherein one of R1 and R3 is a halogen is atom, a Ci-g alkyl group optionally substituted by halogen or a

Ci-6 alkoxy group optionally substituted by halogen, and the other is a hydrogen atom, a halogen atom, a Ci_6 alkyl group optionally substituted by halogen or a Ci_6 alkoxy group optionally substituted by halogen, R2 is a hydrogen atom, a 20 halogen atom, a Ci-g alkyl group optionally substituted by halogen or a Ci-e alkoxy group optionally substituted by halogen, R4 and R6 are each a hydrogen atom, a halogen atom or a Ci_fi alkyl group optionally substituted by halogen, R5 is a hydrogen atom, a halogen atom, a Ci_G alkyl group optionally substituted 25 by halogen or a Ci_6 alkoxy group optionally substituted by halogen, and R7 is a hydrogen atom or a Ci-g alkyl group optionally substituted by halogen, or a salt thereof.

EFFECT OF THE INVENTION

[0020] 30 Compound (I) of the present invention shows a superior proton pump inhibitory effect. Conventional proton pump inhibitors such as omeprazole, lansoprazole and the like are converted to active forms in an acidic environment of gastric parietal cells and form a covalent bond with a cysteine 35 residue of H+/K+-ATPase, and irreversibly inhibit the enzyme 7 WO 2010/024451 PCT/JP2009/065279 activity. In contrast, compound (I) inhibits proton pump (H+/K+-ATPase) activity in a reversible and K+ competitive manner', and consequently suppresses acid secretion. Therefore, it is sometimes called a potassium-competitive acid blocker 5 (P-CAB), or an acid pump antagonist (APA). Compound (I) rapidly exhibits the action and shows the maximum efficacy from the initial administration. Furthermore, its metabolism is less influenced by metabolic polymorphism and variation of efficacy among patients is small. In addition, it has been 10 found that compound (I) is designed to have a characteristic chemical structure wherein (i) the substituent at the 5-position of pyrrole ring is a 2-F-3-pyridyl group, (ii) the substituent at the 4-position of pyrrole ring is a fluorine atom, and (iii) the 1-position of pyrrole ring is a 2- 15 pyridylsulfonyl group or 3-pyridylsulfonyl group having at least one substituent, and such chemical structure is conducive to a strong proton pump inhibitory activity, and significantly decreases cytotoxicity. Furthermore, it is characterized in that substitution of the 4-position of 20 pyrrole ring by a fluorine atom in compound (I) lowers basicity (pKa value) of methylaminomethyl moiety due to an electron withdrawing effect of the fluorine atom, and decreases the risk of toxicity expression derived from strong basicity, and that introduction of at least one substituent 25 into 2-pyridyl group or 3-pyridyl group in A of compound (I) controls the duration of action optimally. Hence, the present invention can provide a clinically useful agent for the prophylaxis or treatment of peptic ulcer (e.g., gastric ulcer, duodenal ulcer, anastomotic ulcer, ulcer caused by non- 30 steroidal anti-inflammatory drug, ulcer due to postoperative stress etc.), Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (Symptomatic GERD), Barrett's esophagus, functional dyspepsia, gastric cancer, stomach MALT lymphoma or 35 hyperacidity; or a suppressant of upper gastrointestinal 8 WO 2010/024451 PCT/JP2009/065279 bleeding due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress; and the like. Since compound (I) shows low toxicity and is superior in water-solubility, in vivo kinetics and efficacy exhibition, it is useful as a 5 pharmaceutical composition. Since compound (I) is stable even under acidic conditions, it can be administered orally as a conventional tablet and the like without formulating into an enteric-coated preparation. This has an advantageous consequence that the preparation (tablet and the like) can be 10 made smaller, and can be easily swallowed by patients having difficulty in swallowing, particularly the elderly and children. In addition, since it is free of a sustained release effect afforded by enteric-coated preparations, onset of suppression of gastric acid secretion is rapid, and symptoms is such as pain and the like can be alleviated rapidly. BRIEF DESCRIPTION OF THE DRAWINGS [0021]

Fig. 1 shows results of perfusate pH measurement test in anesthetized rat stomach perfusion model in Example 2. 20 Fig. 2 shows results of perfusate pH measurement test in anesthetized rat stomach perfusion model in Example 5.

Fig. 3 shows results of perfusate pH measurement test in anesthetized rat stomach perfusion model in Example 24.

[0022] 25 (Detailed Description of the Invention)

In the present specification, examples of the "halogen atom" and "halogen" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. In the formula (I), A is a pyridyl group having at least one substituent. Examples of the 30 "pyridyl group having at least one substituent" for A include a group represented by the formula [0023] 9 WO 2010/024451 PCT/JP2009/065279

(A-2)

[ 0024 J wherein R1, R2 and R3 are each a hydrogen atom, a halogen atom, a Ci-6 alkyl group optionally substituted by halogen or a Ci-6 5 alkoxy group optionally substituted by halogen, R4 and R6 are each a hydrogen atom, a halogen atom or a Ci-s alkyl group optionally substituted by halogen, R5 is a hydrogen atom, a halogen atom, a Ci-β alkyl group optionally substituted by halogen or a Ci_6 alkoxy group optionally substituted by halogen, io and R7 is a hydrogen atom or a Ci-e alkyl group optionally substituted by halogen. By "having at least one substituent" is meant that at least one of R1, R2 and R3 in the partial structure (A—1) is not a hydrogen atom, and at least one of R4, R5, R6 and R7 in the partial structure (A-2) is not a hydrogen is atom.

[0025]

The "Ci-6 alkyl group optionally substituted by halogen" for R1, R2, R3, R4, R5, R6 or R7 is a Ci_6 alkyl group optionally having 1 to 5 (preferably 1 to 3) halogen atoms (e.g., 20 fluorine' atom, chlorine atom, bromine atom, iodine atom), and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, trifluoromethyl and the like. 25 [0026]

The "Ci-6 alkoxy group optionally substituted by halogen" for R1, R2, R3 or R5 is a Ci-e alkoxy group optionally having 1 to 5 (preferably 1 to 3) halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom), and examples 30 thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, 10 WO 2010/024451 PCT/JP2009/065279 •isobutoxy, sec-butoxy, pentyloxy, hexyloxy, fluoromethoxy, trifluoromethoxy and the like.

[0027] R1 is preferably a hydrogen atom or a Ci-e alkyl group 5 optionally substituted by halogen (e.g., methyl, ethyl). R2 is preferably a hydrogen atom, a Ci_6 alkyl group optionally substituted by halogen (e.g., methyl, ethyl), a Ci-6 alkoxy group optionally substituted by halogen (e.g., methoxy, ethoxy). R3 is preferably a hydrogen atom, a halogen atom io (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom), a Ci_g alkoxy group optionally substituted by halogen (e.g., methoxy, ethoxy). R4 is preferably a hydrogen atom, a Ci_6 alkyl group optionally substituted by halogen (e.g., methyl, ethyl). R5 is preferably a hydrogen atom, a halogen atom (e.g., is fluorine atom, chlorine atom, bromine atom, iodine atom), a Ci-g alkyl group optionally substituted by halogen (e.g., methyl, ethyl), a C>6 alkoxy group optionally substituted by halogen (e.g., methoxy, ethoxy). R6 is preferably a hydrogen atom, a Ci-6 alkyl group optionally substituted by halogen (e.g., methyl, 20 ethyl). R7 is preferably a hydrogen atom, a Ci-6 alkyl group optionally substituted by halogen (e.g., methyl, ethyl). R1 is particularly preferably a hydrogen atom or a Ci_6 alkyl group. R2 is particularly preferably a hydrogen atom, a Ci-6 alkyl group or a Ci-e alkoxy group. R3 is particularly 25 preferably a hydrogen atom, a halogen atom or a Ci-6 alkoxy group. R4 is particularly preferably a hydrogen atom or a Ci_6 alkyl group. R5 is particularly preferably a hydrogen atom, a halogen atom or a Cj-6 alkyl group. R6 is particularly preferably a hydrogen atom or a Ci_6 alkyl group. R7 is 30 particularly preferably a hydrogen atom or a Ci_g alkyl group.

In the formula (I), A can be classified into the following embodiments. (i) A is represented by the formula (A-l) wherein both R1 and R3 are hydrogen atoms, R2 is a halogen atom, a Ci-$ alkyl group 35 optionally substituted by halogen or a Ci_6 alkoxy group 11 WO 2010/024451 PCT/JP2009/065279 optionally substituted by halogen. (ii) A is a pyridyl group having at least one substituent, represented by the formula (A-1) or represented by the formula (A-2), wherein one of R1 and R3 is a halogen atom, a Ci-6 alkyl 5 group optionally substituted by halogen or a Ci_6 alkoxy group optionally substituted by halogen, and the other is a hydrogen atom, a halogen atom, a Ci-g alkyl group optionally substituted by halogen or a Ci_g alkoxy group optionally substituted by halogen, R2 is a hydrogen atom, a halogen atom, a Ci_6 alkyl io group optionally substituted by halogen or a Ci-β alkoxy group optionally substituted by halogen, R4 and R5 are each a hydrogen atom, a halogen atom or a Ci_6 alkyl group optionally substituted by halogen, R5 is a hydrogen atom, a halogen atom, a Ci_6 alkyl group optionally substituted by halogen or a Ci_g is alkoxy group optionally substituted by halogen, and R7 is a hydrogen atom or a Ci_6 alkyl group optionally substituted by halogen.

[0028]

Another preferable embodiment of A in the formula (I) is 20 the formula

wherein R1, R2 and R3 are as defined above, and show preferable 25 embodiments of the corresponding substituents in the formula (I) . The pyridyl group of a partial structure <A—3) has, besides methyl group, at least one substituent R1, R2 or R3. In the partial structure (A—3), at least one of R1, R2 and R3 is not a hydrogen atom. 30 As the "pyridyl group having at least one substituent" for A, preferred is the formula 12 PCT/JP2009/065279 WO 2010/024451 [0031]

(A-2W

[0032] wherein R1, R2, R3, R4, R5, R6 and R7 are as defined above, and 5 show preferable embodiments of the corresponding substituents in the formula (I). In a partial structure (A-2a), at least one of R4 and R5 is not a hydrogen atom, and in the partial structure (A-2b), at least one of R6 and R7 is not a hydrogen atom. io [0033]

Particularly preferable embodiment of compound (I) is a compound represented by the following formula (la) or (lb) or a salt thereof.

[0034]

formula (la) [0035] 13 WO 2010/024451 PCT/JP2009/065279

[0036]

Here, preferable embodiments of each substituent in the 5 formulas (la) and (lb) are those of the corresponding substituent in the formula (I).

Particularly preferable other embodiments of compound (I) are compounds represented by the following formula (la-1), the formula (la-2), the formula (lb) and the formula (Ic) and io salts thereof.

[0037]

14 WO 2010/024451 PCT/JP2009/065279

[0041]

Here, preferable embodiments of each substituent in the 10 formulas (la-1), the formula (la-2), the formula (lb) and the formula (Ic> are those of the corresponding substituent in the formula (I) . However, at least one of R1 and R3 in the formula 15 211335/2 (la-1) is not a hydrogen atom, R2 in the formula (la-2) is not a hydrogen atom, at least one of R4 and R5 in the formula (lb) is not a hydrogen atom, and at least one of R6 and R7 in the formula (Ic) is not a hydrogen atom.

[0042]

Specifically, R1 and R3 in the formula (la-1) are the same or different and each is a hydrogen atom, a halogen atom, a Ci-6 alkyl group optionally substituted by halogen or a Ci_g alkoxy group optionally substituted by halogen. Preferred as R1 of the formula (la-1) is a hydrogen atom or a Ci-g alkyl group optionally substituted by halogen, particularly preferably a hydrogen atom or a Ci-g alkyl group. Preferred as R3 of the formula (la-1) is a hydrogen atom, a halogen atom or a Ci-6 alkoxy group optionally substituted by halogen, particularly preferably a hydrogen atom, a halogen atom or a Ci-g alkoxy group.

[0043] R2 of the formula (la-2) is a halogen atom, a Ci-g alkyl group optionally substituted by halogen or a Ci-6 alkoxy group optionally substituted by halogen. Preferred as R2 of the formula (la-2) is a Ci_6 alkyl group optionally substituted by halogen or a Ci-g alkoxy group optionally substituted by halogen, particularly preferably a Ci_6 alkyl group or a Ci-g alkoxy group. [0044] R4 of the formula (lb) is a hydrogen atom, a halogen atom or a Ci-g alkyl group optionally substituted by halogen.

Preferred as R4 is a hydrogen atom or a Ci-g alkyl group optionally substituted by halogen, particularly preferably a hydrogen atom or a Ci-6 alkyl group. R5 of the formula (lb) is a hydrogen atom, a halogen atom, a Ci-g alkyl group optionally substituted by halogen or a Ci_g alkoxy group optionally substituted by halogen. Preferred as R5 is a hydrogen atom, a halogen atom or a Ci-g alkyl group optionally substituted by halogen, particularly preferably a 16 WO 2010/024451 PCT/JP2009/065279 hydrogen atom, a halogen atom or a C;-g alkyl group.

[0045] R6 of the formula (Ic) is a hydrogen atom, a halogen atom or a Ci-6 alkyl group optionally substituted by halogen. 5 Preferred as R6 is a hydrogen atom or a Ci-6 alkyl group optionally substituted by halogen, particularly preferably a hydrogen atom or a Ci_e alkyl group. R7 of the formula (Ic) is a hydrogen atom or a Ci-e alkyl group optionally substituted by halogen. Preferred as R7 is a io hydrogen atom or a Ci-β alkyl group optionally substituted by halogen, particularly preferably a hydrogen atom or a Ci-6 alkyl group.

[0046]

Among those mentioned above, the formula (la-2) is 15 particularly preferable.

[0047]

Of compounds (I), the following compounds are preferable. 1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-lH-pyrrol-3-yl)-N-methylmethanamine or a salt 20 thereof, 1~{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-lH-pyrrol-3-yl]-N-methylmethanamine or a salt thereof, l-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-2-25 yl)sulfonyl]-lH-pyrrol-3-yl[-N-methylmethanamine or a salt thereof, 1—{4-fluoro—5—(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl>sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, 30 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl]-N-methylmethanamine or a salt thereof, 1—{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine or a salt 35 thereof, 17 WO 2010/024451 PCT/JP2009/065279 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3- yl)sulfonyl]-lH~pyrrol-3-yl}-N-methylmethanamine or a salt thereof, 1—{4-fluoro-5-(2-fluoropyridin-3-yl)-1- [(6-methylpyridin-3- 5 yl)sulfonyl]-lH~pyrrol-3-yl}-N-methylmethanamine or a salt thereof, . l-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, io 1—{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methoxypyridin-2-yl)sulfonyl]-lH-pyrrol-3-yl]-N-methylmethanamine or a salt thereof, 1—{1-[(5-chloropyridin-3-yl)sulfonyl]-4-fluoro-S-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl}-N-methylmethanamine or a is salt thereof, l-{4-fluoro-l-[(5-fluoro-6-methylpyridin-2-yl)sulfonyl]-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, l-{4-fluoro-l-[(5-fluoro-4-methylpyridin-2-yl)sulfonyl]-5-¢2- 20 fluoropyridin-3-yl)-lH-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, l-{4-fluoro-l-[(5-fluoro-4-methoxypyridln-2-yl)sulfonyl]-5-(2 fluoropyridin-3-yl)-lH-pyrrol-3-yl]-N-methylmethanamine or a salt thereof, 25 l-{4-fluoro-5-{2-fluoropyridin-3-yl)-1-[(5-methoxypyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, 1-{4-fluoro-l-[i5-fluoro-6-methylpyridin-3-yl)sulfonyl]-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl]-N-methylmethanamine or a 30 salt thereof, l-{1-[(4,6-dimethylpyridin-2-yl)sulfonyl]-4-fluoro-5-¢2-fluoropyridin-3-yl)-lH-pyrrol-3-yl]-N-methylmethanamine or a salt thereof, 1—{1— [ (5-chloropyridin-2-yl)sulfonyl]-4-fluoro-5-(2- 35 fluoropyridin-3-yl)-lH-pyrrol-3-yl]-N-methylmethanamine or a 18 WO 2010/024451 PCT/JP2009/065279 salt thereof, 1-{1-[(5,6-dimethylpyridin-2-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl]-N-methylmethanamine or a salt thereof, 5 1-{1- [ ¢4,5-dimethylpyridin-2-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl]-N-methylmethanamine or a salt thereof, and l-{4-fluoro-5-[2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl) sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine or a salt io thereof.

[0048]

As compound (I), the following compounds are particularly preferable. 1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin~2- 25 yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-2-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, 20 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-lH-pyrrol-3-yl]-N-methylmethanamine or a salt thereof, l-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-lH-pyrrol-3-yli-N-methylmethanamine or a salt 25 thereof, and l-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine or a salt thereof.

[0049] 30 Examples of the salt of compound (I) include metal salt, ammonium salt, salts with organic bases, salts with inorganic bases, salts with organic acids, salts with basic or acidic amino acids and the like. Preferable examples of metal salt include alkali metal salts such as sodium salt, potassium salt 35 and the like; alkaline earth metal salts such as calcium salt, 19 WO 2010/024451 PCT/JP2009/065279 magnesium salt, barium salt and the like; aluminum salt and the like. Preferable examples of the salt with organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, 5 triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with io 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, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and the like. Preferable examples of the 25 salt with basic amino acid include a salt with arginine, lysin, ornithine and the like. Preferable examples of the salt with acidic amino acid include a salt with aspartic acid, glutamic acid and the like. Of these, pharmaceutically acceptable salts are preferable. For example, when a compound contains an 20 acidic functional group, inorganic salts such as alkali metal salt (e.g., sodium salt, potassium salt etc.), alkaline earth metal salt (e.g., calcium salt, magnesium salt, barium salt etc.) and the like, ammonium salt and the like can be mentioned; and when a compound contains a basic functional 25 group, for example, salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, or salts with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, 30 methanesulfonic acid, p-toluenesulfonic acid and the like can be mentioned.

[0050] .

The production methods of compound (I) in the present invention are explained. The compounds (II)-(XXXIII) in the 35 formula may form salts, and as such salts, for example, those 20 WO 2010/024451 PCT/JP2009/065279 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 purified from 5 the reaction mixture by a known separation and purification means, such as recrystallization, distillation, chromatography and the like.

[0051]

[0052]

Compound <TI> wherein R8 is a Ci-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl and the like can be produced according to a method known per se, such as the is 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.

[0053]

Compound (III) wherein each symbol is as defined above 20 can be produced by fluorinating compound (II) with a fluorinating reagent such as N-fluoropyridinium salt, xenon difluoride and the like. The amount of the fluorinating reagent to be used is 0.75 - 10 equivalents, preferably 1-5 equivalents, relative to compound (II). This reaction is 25 advantageously carried out using a solvent inert to the reaction. While the solvent is not particularly limited as 21 WO 2010/024451 PCT/JP2009/065279 long as the reaction proceeds, hydrocarbons such as benzene, toluene and the like, tetrahydrofuran, diethyl ether, acetonitrile and the like or a mixed solvent thereof and the like is preferable. While the reaction time varies depending on the reagents and solvent to be used, it is generally 10 min to 24 hr, preferably 30 min to 12 hr. The reaction temperature is generally -78°C to 100°C, preferably -20°C to 60°C. In addition, it is possible to introduce a fluorine group by stepwise reactions, for example, bromination with N-bromosuccinimide (NBS) and the like, followed by conversion to a fluorine group by substitution reaction.

[0054]

Compound (IV) can be produced by reducing compound (III) with a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, calcium borohydride and the like. As the reducing agent, diisobutylaluminum hydride is particularly preferable. The amount of the reducing agent to be used is 0.75 - 10 equivalents, preferably 1-5 equivalents, relative to compound (III).

[0055]

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 hydrocarbons such as benzene, toluene and the like, ethers such as tetrahydrofuran, diethyl ether, etc. and the like and a mixed solvent thereof and the like are preferable. While the reaction time varies depending on the reagents and solvents to be used, it is generally 10 min to 24 hr, preferably 30 min to 8 hr. The reaction temperature is generally -78°C to 100°C, preferably -78°C to 25°C.

[0056]

Compound (V) can be produced by reacting compound (IV) with an oxidant such as chromic acid-pyridine complex, pyridinium chlorochromate, manganese dioxide, sulfur trioxide- 22 WO 2010/024451 PCT/JP2009/065279 pyridine complex, tetra-n-propylammonium perruthenate and the like- As the oxidant, manganese dioxide, sulfur trioxide- pyridine complex or tetra-n-propylammonium perruthenate is preferable. This oxidation reaction can be performed, for 5 example, according to the method described in Synthesis, p. 639 (1994).

Compound (VII) can be produced by reacting compound (V) with a compound represented by the formula (VI) (0057]

O

II

A—S—X

II o ίο (VI) [0058] wherein X is a halogen atom such as a fluorine atom, a chlorine atom and the like, and the other symbol is as defined above. The amount of compound (VI) to be used is 0.75 - 10 mol, 15 preferably 1-3 mol, per 1 mol of compound (V).

[0059]

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, 20 hydrocarbons such as benzene, toluene and the like, ethers such as tetrahydrofuran and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like, acetonitrile and the like or a mixed solvent thereof and the like are preferable. 25 [0060]

Use of a base is effective for the reaction. As the base, for example, inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, 30 sodium hydrogen carbonate and the like, metal bases such as potassium ethoxide, potassium tert-butoxide, sodium methoxide, 23 WO 2010/024451 PCT/JP2009/065279 sodium ethoxide and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4- dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, 5 N-methylpyrrolidine, N-methylmorpholine and the like, and the like can be mentioned. The amount of the base to be used is 0.8 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (V) . The reaction can also be carried out and is advantageous in the co-presence of a crown ether. As the crown ether, for io example, 15-crown-5-ether, 18-crown-6-ether and the like can be mentioned. The amount of the crown ether to be used is 0.01 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (V). While the reaction time varies depending on the reagents and solvent to be used, it is generally 1 min to 48 hr, preferably 25 10 min to 8 hr. The reaction temperature is generally -20°C to 100°C, preferably 0°C to 50°C.

[0061]

Compound (I) wherein each symbol is as defined above can be produced using compound (VII) and methylamine or a salt 20 thereof, by a reductive amination reaction analogous to the method described in Jikken Kagaku Koza (Courses in Experimental Chemistry), vol. 14-III, p. 1380 - 1385 (published by MARUZEN CO., LTD.) and the like. In addition, compound (II) can also be produced according to the following 25 method, and compound (I) can be produced using a method similar to the method described above.

[0062] 24 WO 2010/024451 PCT/JP2009/065279

(II) [0063]

Compound (VIII) wherein each symbol is as defined above can be produced according to a method known per se, for 5 example, the methods described in Tetrahedron Letters, vol. 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. [0064] 20 Compound (IX) wherein each symbol is as defined above can be produced by reacting compound (VIII) with N-bromosuccinimide (NBS). N-Bromosuccinimide (NBS) is preferably used in about one equivalent relative to compound (VIII), and the reaction is preferably carried out under an inert gas 15 atmosphere such as nitrogen, argon and the like.

[0065]

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, 20 solvents such as ethers (e.g., tetrahydrofuran, diethyl ether and the like), amides (e.g., Ν,Ν-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 25 generally 10 min to 24 hr, preferably 5 to 12 hr. The reaction 25 WO 2010/024451 PCT/JP2009/065279 temperature is generally -78°C to 80°C, preferably -78°C to 30°C [0066]

Addition of a base is sometimes effective for the reaction. While the base to be used is not limited as long as 5 the reaction proceeds, organic bases such as pyridine, picoline, lutidine and the like, and the like can be mentioned The amount of the organic base to be used is 0.001 to 10 equivalents, preferably 0.001 to 0.1 equivalent, per compound (VIII). io [0067]

Compound (X) wherein R9 is a pyrrole-protecting group and other symbols are as defined above can be produced by protecting pyrrole nitrogen of compound (IX). The pyrroleprotecting group is not particularly limited, and examples is thereof include a tert-butoxycarbonyl group (BOC group), a benzyloxycarbonyl group (Cbz group), an aryl or a heteroarylsulfonyl group, a benzyl group, a triisopropylsilyl group and the like.

[0068] 20 This protection reaction can be performed according to a method known per se, for example, a method analogous to 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. 25 [0069]

Compound (XII) wherein each symbol is as defined above can be produced by reacting compound (X) with a compound represented by the formula (XIa) [0070] 30

[0071] 26 WO 2010/024451 PCT/JP2009/065279 wherein each symbol is as defined above, or various ester derivatives of the formula (XIa) according to the method described in Synthetic Communications, vol. 11, page 513 (1981), or a method analogous thereto. In addition, can be 5 produced by reacting compound (X) with a compound represented by the formula (Xlb)

<Xlb> [0073] io wherein R is an alkyl group or an aryl group, according to the method described in Synthesis, vol. 7, pages 564-565 ¢1986) or a method analogous thereto. Examples of the "alkyl'group" for R include a methyl group and an n-butyl group, and examples of the "aryl group" include a phenyl group. 15 [0074]

Compound (II) wherein each symbol is as defined above can be produced from compound (IX) according to a method similar to the method for producing compound (XII) from compound (X). Alternatively, compound (II) can be produced from compound 20 (XII) 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, by removing a pyrrole nitrogen-protecting group. In addition, compound (I) can also 25 be produced according to the following method.

[0075] 27 WO 2010/024451 PCT/JP2009/065279

[0076]

Compound (XIII) wherein each symbol is as defined above can be produced from compound (III) according to a method 5 similar to the method for producing compound (VII) from compound (V).

[0077]

Compound (XIV) wherein each symbol is as defined above can be produced from compound (XIII) according to a method io similar to the method for producing compound (IV) from compound (III).

[0078]

Compound (VII) wherein each symbol is as defined above can be produced from compound (XIV) according to a method 15 similar to the method for producing compound (V) from compound (IV) .

[0079]

Compound (I) can be produced from compound (VII) by a method similar to the method described above. Alternatively, 20 compound (I) can also be produced from compound (XIV) according to a method including reacting methylamine via halogenation and methanesulfonylation, a method including condensing with methylamine protected by Boc, etc., followed by deprotection and the like. In addition, compound (I) can 28 WO 2010/024451 PCT/JP2009/065279 also be produced according to the following method.

[0080]

reduc tive amina tion

deprotec tion -* fl>

[0081] 5 Compound (XV) as defined above can be produced from compound (V) according to a method similar to the method for producing compound (I) from compound (VII).

[0082]

Compound (XVI) wherein R10 is an amino-protecting group io can be produced by protecting the amino group of compound (XV)

Examples of the amino-protecting group include, but is not particularly limited to, a tert-butoxycarbonyl group (BOC group), a benzyloxycarbonyl group (Cbz group), a 2,4-dimethoxybenzyl group and the like. This protection reaction is can be carried out according to 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.

[0083] 20 Compound (XVII) wherein each symbol is as defined above can be produced from compound (XVI) according to a method similar to the, method for producing compound (VII) from compound (V).

[0084] 25 Compound (I) can be produced by removing the amino protecting group from compound (XVII) by a method known per se for example, the method described in Protective Groups in 29 WO 2010/024451 PCT/JP2009/065279

Organic Synthesis, 3rd Ed., Theodora W. Greene, Peter G. M.

Wuts, pp. 494-653, Wiley-Interscience (1999) and the like.

Compound (V) can also be produced by the following method.

Furthermore, compound (I) can be produced using a method 5 similar to the method described above.

[0085]

fluorina tion [0086]

Compound (XVIII) can be produced according to a method io known per se, for example, the method described in Journal of

Organic Chemistry (J. Org. Chem.), vol. 55, p. 6317 (1990) and the like, or a method analogous thereto.

[0087]

Compound (XIX) wherein each symbol is as defined above 15 can be produced from compound (XVIII) according to a method similar to the method for producing compound (X) from compound (IX) .

[0088]

Compound (XX) wherein each symbol is as defined above can 20 be produced from compound (XIX) according to a method similar to the method for producing compound (XII) from compound (X).

[0089]

Compound (XXI) can be produced from compound (XX) according to a method similar to the method for producing 25 compound (II) from compound (XII). Alternatively, compound (XXI) wherein each symbol is as defined above can be produced 30 WO 2010/024451 PCT/JP2009/065279 from compound (XVIII) according to a method similar to the method for producing compound (XII) from compound (X).

[0090]

Compound (V) can be produced from compound (XXI) according to a method similar to the method for producing compound (III) from compound (II). In addition, compound (V) can also be produced according to the following method. Further, compound (I) can be produced using a method similar to the method described above.

[0091]

(XXVII) (XXVIII) (V) [0092]

Compound (XXII) wherein each symbol is as defined above can be produced according to a method known per se, for example, the method described in Tetrahedron Letters, vol.40, p. 4905-4908 (1999) and the like, or a method analogous thereto.

[0093]

Compound (XXIII) wherein R11 is a hydroxy-protecting group, and other symbols are as defined above can be produced, for example, according to the method described in Organic Biomolecular Chemistry (Org. Biomol. Chem.), vol. 1, p. 3527-3534 ¢2003) and the like by reacting compound (XXII) with bromo(or chloro, iodo)difluoroacetic acid ester, and protecting the resulting hydroxy group. The hydroxy-protecting group is not particularly limited as long as the reaction proceeds, and preferable examples include a tosyl group, a mesyl group and the like. 31 WO 2010/024451 PCT/JP2009/065279 [0094]

Compound (XXIV) wherein R12 is an amide-protecting group, and other symbols are as defined above can be produced by subjecting compound (XXIII) to cyclization reaction via 5 deprotection of an amino group, and protecting the amide group. The conditions of the amino group deprotection and cyclization are not particularly limited as long as the reaction proceeds, and examples thereof include reaction conditions for simultaneous cyclization and deprotection in a hydrogen io chloride-ethyl acetate solution and the like. The amide protecting group is not limited as long as the reaction proceeds, and preferable examples include a tertbutoxycarbonyl group (BOC group) and the like.

[0095] is Compound (XXVI) wherein each symbol is as defined above can be produced by reacting compound (XXIV) with a compound represented by the formula (XXV) wherein Z is an atom or molecule imparting nucleophilicity such as Li, MgBr and the like. 20 [0096]

F (XXV) [0097]

Compound (XXV) can be produced in a reaction system according to, for example, the method described in Tetrahedron 25 Lett., vol. 21, p. 4137 (1980) or Tetrahedron Lett., vol. 42, p. 8697 (2001), or a method analogous thereto.

[0098]

The solvent of this reaction is not particularly limited as long as the reaction proceeds, and preferable solvents 30 include hydrocarbons such as n-hexane, toluene and the like, ethers such as tetrahydrofuran, diethyl ether and the like and the like or a mixed solvent thereof and the like. The reaction 32 211335/2 time varies depending on the substrate and solvent to be used, and is generally 1 min to 48 hr, preferably 10 min to 24 hr. [0099]

Compound (XXVII) can be produced according to a method known per se, for example, the method described in'Tetrahedron Letters, vol. 36, p. 5119-5122 (1995) and the like, or a method analogous thereto. Alternatively, compound (XXVII) can be produced by reducing compound (XXVI) and reacting the resulting compound with a base. The reducing agent to be used for this reaction is not particularly limited as long as the reaction proceeds, and preferable examples include sodium borohydride and the like.

[0100]

Examples of the base include inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and the like, metal bases such as potassium ethoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide and the like, aromatic amines such 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, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and the like, and the like. The amount of the bases to be used is 0.8 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (XXVI).

[0101]

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, ethers such as tetrahydrofuran and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like, acetonitrile and the like or a mixed solvent thereof and the 33 WO 2010/024451 PCT/JP2009/065279 like is preferable. This reaction is advantageous in that it can be performed in the co-presence of crown ethers. Examples of the crown ether include 15-crown-5-ether, 18-crown-6-ether and the like. The amount of the crown ether to be used is 0.01 s to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (XXVI) While the reaction time varies depending on the reagents and solvent to be used, it is generally 1 min to 48 hr, preferably 10 min to 8 hr. The reaction temperature is generally -78°C to 100°C, preferably -10°C to 70°C. 10 [0102]

Compound (XXVIII) wherein each symbol is as defined above can be produced from compound (XXVII) according to a method similar to the method for producing compound (X) from compound (IX) . is [0103]

Compound (V) can be produced from compound (XXVIII), for example, by a typical formylation reaction including treating a reaction product of oxalyl chloride with dimethylformamide, and the like. In addition, compound (V) can be produced by a 20 method including introducing a cyano group and carboxylic acid and converting the resulting compound to aldehyde and the like In addition, compound (XVI) can also be produced according to the following method, and compound (I) can be produced using a· method similar to the method described above. 25 [0104] 34 WO 2010/024451 PCT/JP2009/065279

[0105]

Compound (XXIX) wherein R12 is as defined above, and R13 is a halogen atom such as a chlorine atom, a bromine atom, an 5 iodine atom and the like can be produced according to a method known per se, for example, the method described in Journal of Organic Chemistry (J. Org. Chem.), vol. 66, p. 315 [2001) and the like, or a method analogous thereto. Examples of the amide-protecting group for R12 include, but is not particularly io limited to, a tert-butoxycarbonyl group (BOC group), a tosyl group, a benzyl group, an allyl group and the like.

[0106]

Compound (XXX) wherein each symbol is as defined above can be produced by treating compound (XXIX) with a base. is Examples of the base include inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and the like, metal bases such as potassium ethoxide, potassium tert- 20 butoxide, sodium methoxide, sodium ethoxide and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4- dimethylaminopyridine, Ν,Ν-dimethylaniline, N-methylpiperidine, 25 N-methylpyrrolidine, N-methylmorpholine, 1,8- 35 WO 2010/024451 PCT/JP2009/065279 diazabicyclo[5.4.0]undec-7-ene(DBU), etc. and the like. The amount of the base to be used is 0.8 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (XXIX).

[0107] 5 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, ethers such as tetrahydrofuran and the like, amides such as N,N- 10 dimethylformamide, Ν,Ν-dimethylacetamide and the like, acetonitrile and the like or a mixed solvent thereof and the like is preferable. While the reaction time varies depending on the reagents and solvent to be used, it is generally 1 min to 48 hr, preferably 10 min to 8 hr. The reaction temperature 15 is generally -78°C to 100°C, preferably -10°C to 70°C.

[0108]

Compound (XXXIa) wherein each symbol is as defined above or compound (XXXIb) wherein each symbols in the formula is as defined above can be produced from compound (XXX) according to 20 a method similar to the method for producing compound (XXVI) from compound (XXIV).

[0109]

Compound (XXXII) can be produced by subjecting compound (XXXIa) or compound (XXXIb) to deprotection and dehydrating 25 reaction. While the reaction condition is not particularly limited, it varies depending on the kind of the protecting group and the solvent to be used. For example, the deprotection and the dehydrating reaction continuously proceed by treating with an acid such as trifluoroacetic acid and 30 hydrochloric acid.

[0110]

Compound (XVI) wherein each symbol is as defined above can be produced by treating a compound represented by the formula (XXXIII) wherein each symbol is as defined above with 35 a base such as sodium hydride, n-butyllithium and the like and 36 reacting the resulting compound with compound (XXXII).

[0111] WO 2010/024451 PCT/JP2009/065279 5*3

(XXXIII) [0112] 5 The protecting group for R10 in this reaction is not particularly limited as long as it is removable, and preferable examples include a benzyl group, a 4-methoxybenzyl group, a 2,4-dimethoxybenzyl group and the like.

[0113] io While the solvent used for this reaction is not particularly limited as long as the reaction proceeds, hydrocarbons such as n-hexane, toluene and the like, ethers such as tetrahydrofuran, diethyl ether and the like or a mixed solvent thereof and the like are preferable. While the is reaction time varies depending on the substrates and solvent to be used, it is generally 1 min to 48 hr, preferably 10 min to 5 hr. The reaction temperature is generally -100°C to 100°C preferably -78°C to 30°C.

[0114] 20 Compound (I) can be isolated and purified by a known 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 25 desired salt by a method known per se or a 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.

[0115] 30 Compound (I) may be used as a prodrug. The prodrug of compound (I) means a compound which is converted to compound (I) under the physiological condition in the body by a 37 WO 2010/024451 PCT/JP2009/065279 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 which is converted to compound (I) by hydrolysis with gastric 5 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 compound (I) is modified with eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-l,3-dioxolen-4- 10 yljmethoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl or t-butyl, etc.); a compound wherein the hydroxy group of compound (I) is modified with acyl, alkyl, phosphoric acid or boric acid (e.g., a compound wherein the hydroxy group of compound (I) is modified with acetyl, 15 palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl or dimethylaminomethylcarbonyl, etc.); a compound wherein a carboxyl group of compound (I) is modified to ester or amide (e.g., a compound wherein a carboxyl group of compound (I) is modified to ethyl ester, phenyl ester, carboxymethyl ester, 20 dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (S-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester, cyclohexyloxycarbonylethyl ester or methylamide, etc.); and the like. These compounds can be produced from compound (I) by a method known per se. In 25 addition, the prodrug of compound (I) may be a compound, which is converted to compound (I) under the physiological conditions, as described in Pharmaceutical Research and Development, Vol. 7 (Molecule Design), pp. 163-198 (1990), published by Hirokawa Publishing Co. 30 (0116]

When compound (I) contains an optical isomer, a stereoisomer, a regioisomer or a rotamer, all of these isomers and a mixture of these are also encompassed in compound (I).

For example, when compound (I) has an optical isomer, an 35 optical isomer resolved from a racemate is also encompassed in 38 WO 2010/024451 PCT/JP2009/065279 compound (I). These isomers can be obtained as single products according to synthesis and separation methods known per se (concentration, solvent extraction, column chromatography, recrystallization, etc.). 5 [0117]

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. io [0118]

Compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate, both of which are encompassed in the compound (I) [0119]

. A compound labeled with an isotope (e.g., 3H, 14C, 35S, is 125I and the like) and a deuterium conversion form wherein lH has been converted to 2H(D) are also encompassed in the compound (I) .

[0120]

Compound (I) or a salt thereof or a prodrug thereof of 20 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., acute toxicity, chronic toxicity, genetic toxicity, 25 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 like), and efficacy exhibition, they are useful as medicaments. 30 [0121]

The compound of the present invention is useful for the prophylaxis or treatment of peptic ulcer (e.g., gastric ulcer, duodenal ulcer, anastomotic ulcer, ulcer caused by nonsteroidal anti-inflammatory drug, ulcer due to postoperative 35 stress etc.); Zollinger-Ellison syndrome; gastritis; erosive 39 WO 2010/024451 PCT/JP2009/065279 esophagitis; reflux esophagitis such as erosive reflux esophagitis and the like; symptomatic gastroesophageal reflux disease (Symptomatic GERD) such as nonerosive esophageal reflux, esophageal reflux unaccompanied by esophagitis and the 5 like; Barrett's esophagus; functional dyspepsia; gastric cancer (including gastric cancer associated with promoted production of interleukin-ΐβ due to gene polymorphism of interleukin-1); stomach MALT lymphoma; hyperacidity; upper gastrointestinal bleeding caused by peptic ulcer, acute stress 10 ulcer, hemorrhagic gastritis, invasive stress (e.g., stress caused by major surgery requiring post-operative intensive management, or cerebrovascular disorder, head injury, multiple organ failure or extensive burn requiring intensive treatment) and the like; airway disorders; asthma; and the like in is mammals (e.g., human, monkey, sheep, bovine, horse, dog, cat, rabbit, rat, mouse etc.), pre-anesthetic administration, eradication or assisting eradication of Helicobacter pylori and the like. As used herein, the above-mentioned reflux esophagitis (erosive esophagitis) and symptomatic 20 gastroesophageal reflux disease (symptomatic GERD) are sometimes collectively referred to simply as GERD.

[0122)

The content of a compound of the present invention in the pharmaceutical composition of the present invention is about 25 0.01 to 100% by weight relative to the entire composition. 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 30 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.

[0123] 35 The compound of the present invention shows low toxicity 40 WO 2010/024451 PCT/JP2009/065279 and can be safely 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 5 admixed according to a method known per se, such as tablets (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 20 and the like. Particularly, the compound of the present invention is preferably administered as an oral preparation in the form of tablet, granule, capsule and the like.

[0124]

The pharmacologically acceptable carrier that may be used 25 to produce the pharmaceutical composition of the present invention includes various organic or inorganic carrier substances in common use as pharmaceutical materials, including excipients, lubricants, binders, disintegrants, water-soluble polymers and basic inorganic salts for solid 20 preparations; and solvents, solubilizing agents, suspending agents, isotonizing agents, buffers and soothing agents for liquid preparations and the like. Ordinary pharmaceutical additives such as preservatives, anti-oxidants, colorants, sweetening agents, souring agents, bubbling agents and 25 flavorings may also be used as necessary. Such "excipients" include, for example, lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light anhydrous silicic acid, titanium oxide and the like. Such "lubricants" include, for example, magnesium stearate, sucrose fatty acid esters, 30 polyethylene glycol, talc, stearic acid and the like. 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. Such 35 "disintegrants" include (1) crosspovidone, (2) what is called 41 WO 2010/024451 PCT/JP2009/065279 super-disintegrants such as crosscarmellose sodium (manufactured by FMC-Asahi Chemical Industry Co. Ltd.) and carmellose calcium (manufactured by Gotoku Yakuhin) etc, (3) sodium carboxymethyl· starch (e.g., product of Matsutani 5 Chemical), (4) low-substituted hydroxypropyl 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 l-ethenyl-2-pyrrolidinone homopolymer, including polyvinylpyrrolidone (PVPP) and l-vinyl-2-pyrrolidinone io homopolymer, and is exemplified by Colidon CL (registered trademark; produced by BASF), Polyplasdon XL (registered trademark; produced by ISP), Polyplasdon XL-10 (registered trademark; produced by ISP), Polyplasdon INF-10 (registered trademark; produced by ISP) and the like. Such "water-soluble 15 polymers" include, for example, ethanol-soluble water-soluble polymers [e.g., cellulose 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 20 hydroxypropylmethyl cellulose (hereinafter also referred to as HPMC)· etc., methyl cellulose, 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 25 of sodium, potassium, magnesium and/or calcium. Preferred are basic inorganic salts of magnesium and/or calcium. More preferred are basic inorganic salts of magnesium. Such basic inorganic salts of sodium include, for example, sodium carbonate, sodium hydrogen carbonate, disodium 30 hydrogenphosphate and the like. Such basic inorganic salts of 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, 35 magnesium aluminometasilicate, magnesium silicate, magnesium 42 WO 2010/024451 PCT/JP2009/065279 aluminate, synthetic hydrotalcite [MgeAl2 (OH) i6 . CO3 . 4H2O], and aluminum magnesium hydroxide. Preferred are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like. Such basic inorganic salts of calcium s include, for example, precipitated calcium carbonate, calcium hydroxide, etc. Such "solvents" include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Such "solubilizing agents" include, for example, polyethylene glycol, propylene glycol, 10 D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Such "suspending agents" include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium 15 chloride, benzethonium chloride, glyceryl monostearate etc; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose etc., and the like. Such "isotonizing 20 agents" include, for example, glucose, D-sorbitol, sodium chloride, glycerol, D-mannitol and the like. Such "buffers" include, for example, buffer solutions of phosphates, acetates, carbonates, citrates etc, and the like. Such "soothing agents" include, for example, benzyl alcohol and the like. Such 25 "preservatives" include, for example, p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Such "antioxidants" include, for example, sulfites, ascorbic acid, α-tocopherol and the like. Such "colorants" include, for 30 example, food colors such as Food Color Yellow No. 5, Food Color Red No. 2, Food Color Blue No. 2 etc.; food lake colors, 'red ferric oxide and the like. Such "sweetening agents" include, for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like. 35 Such "souring agents" include, for example, citric acid 43 WO 2010/024451 PCT/JP2009/065279 (citric anhydride), tartaric acid, malic acid and the like.

Such "bubbling agents" include, for example, sodium bicarbonate and the like. Such "flavorings" may be synthetic substances or naturally occurring substances, and include, for 5 example, lemon, lime, orange, menthol, strawberry and the like (0125]

The compound of the present invention may be prepared as a preparation for oral administration in accordance with a commonly-known method, by, for example, compression-shaping 10 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 release. For an enteric preparation, an intermediate layer may is 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.

[0126]

For preparing the compound of the present invention as an 20 orally disintegrating tablet, available methods include, for 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 an 25 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 30 mannitol to give fine granules, which are mixed with additives and shaped.

[0127]

The above-mentioned "enteric coating layer" includes,· for example, a layer consisting of a mixture of one or more kinds 35 from aqueous enteric polymer substrates such as cellulose 44 WO 2010/024451 PCT/JP2009/065279 acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, methacrylic acid copolymers (e.g., Eudragit (registered trademark; produced by Rohm) L30D-55, Colicoat (registered 5 trademark; produced by BASF) MAE30DP, Polyquid (registered trademark; produced by San-yo Chemical) PA30 etc.), carboxymethylethyl cellulose, shellac and the like; sustained-release substrates such as methacrylic acid copolymers (e.g., Eudragit (registered trademark) NE30D, Eudragit (registered 10 trademark) RL30D, Eudragit (registered trademark) RS30D, etc.) and the like; water-soluble polymers; plasticizers such as triethyl citrate, polyethylene glycol, acetylated monoglycerides, triacetin, castor oil and the like; and the like, and the like. 15 [0128]

The above-mentioned "additive" includes, for example, water-soluble sugar alcohols (e.g., sorbitol, mannitol, maltitol, reduced starch saccharides, xylitol, reduced palatinose, erythritol, etc.), crystalline cellulose (e.g., 20 Ceolas (registered trademark) KG 801, Avicel (registered trademark) PH 101, Avicel (registered trademark) PH 102,

Avicel (registered trademark) PH 301, Avicel (registered trademark) PH 302, Avicel (registered trademark) RC-591 (crystalline cellulose . carmellose sodium) etc.), low- 25 substituted hydroxypropyl cellulose (e.g., LH-22, LH-32, LH-23, LH-33 (Shin-Etsu Chemical), mixtures thereof etc.) and the like. Furthermore, binders, souring agents, bubbling agents, sweetening agents, flavorings, lubricants, colorants, stabilizers, excipients, disintegrants etc. are also used. so [0129]

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, 35 quinolone compounds, and so forth. Examples of the "anti- 45 WO 2010/024451 PCT/JP2009/065279

Helicobacter pylori active substance" include penicillin antibiotic (e.g., amoxicillin, benzylpenicillin, piperacillin, mecillinam, ampicillin, temocillin, bacampicillin, aspoxicillin, sultamicillin, lenampicillin etc.), cephem 5 antibiotic (e.g., cefixime, cefaclor etc.), macrolide antibiotic (e.g., erythromycin, clarithromycin, roxithromycin, rokitamycin, flurithromycin, telithromycin etc.), tetracycline antibiotic (e.g., tetracycline, minocycline, streptomycin etc.), aminoglycoside antibiotic (e.g., gentamicin, amikacin 20 etc.), imipenem and the like. Of these, penicillin antibiotic, macrolide antibiotic and the like are preferable. Such "imidazole compounds" include, for example, metronidazole, miconazole and the like. Such "bismuth salts" include, for example, bismuth acetate, bismuth citrate, bismuth is 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 penicillin antibiotic (e.g., amoxicillin and the like) and erythromycin antibiotic 20 {e.g., clarithromycin and the like) is preferably used.

[0130]

For the purpose of eradication of Helicobacter pylori, while the compound of the present invention has an anti-H. pylori action (bacteriostatic action or eradication action) by 25 itself, it can enhance antibacterial action of other antibiotics based on the pH controlling action in the stomach and the like, and also provides an assisting effect such as an eradication effect based on the action of the antibiotics to be used in combination. Such "other active ingredients" and 30 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), liquids, injectable preparations, suppositories, sustained-release preparations, etc.], in accordance with a 35 commonly known method, and used in combination, and may also 46 WO 2010/024451 PCT/JP2009/065279 be prepared as separate preparations and administered to the same subject simultaneously or at a time interval.

[0131]

In addition, the compound of the present invention may be 5 ' used in combination with a prokinetic drug, a drug acting on lower esophageal sphincter (e.g., transientlower esophageal sphincter relaxation suppressant etc.), C1C-2 channel opener (stimulant of intestinal juice secretion), a histamine H2 receptor antagonist, an antacid, a sedative, a stomachic or a 10 non-steroidal anti-inflammatory drug (NSAID). As the "prokinetic drug", for example, domperidone, metoclopramide, mosapride, itopride, tegaserod 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 15 optically active form thereof and the like, glutamine receptor antagonists and the like can be mentioned. As the "C1C-2 channel opener (stimulant of intestinal juice secretion)", lubiprostone and the like can be mentioned. As the "histamine H2 receptor antagonist", cimetidine, ranitidine, famotidine, 20 roxatidine, nizatidine, lafutidine and the like can be mentioned. As the "antacid", sodium hydrogen carbonate, aluminum hydroxide and the like can be mentioned. As the "sedatives", diazepam, chlordiazepoxide and the like can be mentioned. As the "stomachic", gentiana, swertia japonica, 25 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.

[0132] 30 A prokinetic drug, a drug acting on lower esophageal sphincter, a C1C-2 channel opener (stimulant of intestinal juice secretion), a histamine H2 receptor antagonist, an antacid, a sedative, a stomachic or a non-steroidal antiinflammatory drug and compound (I) or a salt thereof of the 35 present invention may be mixed, prepared as a single 47 WO 2010/024451 PCT/JP2009/065279 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 5 prepared as separate preparations and administered to the same subject simultaneously or in a time-lag manner.

[0133]

The compound of the present invention may be used in combination with the following drugs. io (i) proton pump inhibitor, for example, omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lansoprazole; (ii) oral antacid combination agent, for example, Maalox, Aludrox and Gaviscon; is (iii) mucous membrane protector, for example, polaprezinc, ecabe sodium, rebamipide, teprenone, cetraxate, sucralfate, chloropylline-copper and plaunotol; (iv) antigastric agent, for example, anti-gastrin vaccine, itriglumide and Z-360; 20' (v) 5-HT3 antagonist, for example, dolasetron, palonosetron, alosetron, azasetron, ramosetron, mitrazapine, granisetron, tropisetron, E-3620, ondansetron and indisetron; (vi) 5-HT4 agonist, for example, tegaserod, mosapride, cinitapride and oxtriptane; 25 (vii) laxative agent, for example, Trifyba, Fybogel,

Konsyl, Isogel, Regulan, Celevac and Normacol; (viii) GABAb agonist, for example, baclofen and AZD-3355; (ix) GABAb antagonist, for example, GAS-360 and SGS-742; (x) calcium channel blocker, for example, aranidipine, 30 lacidipine, falodipine, azelnidipine, clinidipine, lomerizine, diltiazem, gallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine, bevantolol, nicardipine, isradipine, benidipine, verapamil, nitrendipine, barnidipine, propafenone, manidipine, bepridil, nifedipine, nilvadipine, nimodipine and fasudil; 35 (xi) dopamine antagonist, for example, metoclopramide, 48 PCT/JP2009/065279 WO 2010/024451 domperidone and levosulpiride; (xii) tachykinin (NK) antagonist, particularly, NK-3, NK- 2 and NK-1 antagonist, for example, nepadutant, saredutant, talnetant, (aR,9R)-7-(3,5-bis(trifluoromethyl)benzyl]- 5 8,9,10,ll-tetrahydro-9-methyl-5-(4-methylphenyl)-7H- [1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3- (4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-l,2,4-triazol-3-one (MK-869), lanepitant, dapitant and (2S,3S)-3- 10 [[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenyl- piperidine; (xiii) nitric monoxide synthase inhibitor, for example, GW-274150, tilarginine, P54, guanidioethyldisulfide and nitroflurbiprofen; is (xiv) vanilloid receptor 1 antagonist, for example, AMG- 517 and GW-705498; (xv) ghrelin agonist, for example, capromorelin and TZP- 101; (xvi) AChE inhibitor, for example, Z-338 and KW-5092. 20 [0134]

The above-mentioned drugs (i)-(xvi) and 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), liquids,

25 injections, suppositories, sustained-release preparations, etc.] according to a method known per se for combined use, or may also be prepared as separate preparations and administered to the same subject simultaneously or in a time-lag manner. EXAMPLES 30 [0135]

The present invention is explained in detail in the following by referring to Reference Examples,· Examples and Experimental Examples, which are not to be construed as limitative. 35 [0136] 49 WO 2010/024451 PCT/JP2009/065279

In the following Reference Examples and Examples, the "room temperature" generally means about 10°C to about 35°C,-but it is not particularly strictly limited. The mixing ratio of liquids shows a volume ratio. Unless otherwise specified, 5 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, Fuji Silysia Chemical Ltd. Chromatorex (trade name) NH (described as basic silica gel column chromatography) or Purif-Pack manufactured by io MORITEX (described as silica gel column chromatography or 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 1H-NMR spectrum, is tetramethylsilane was used as the internal standard, and

Varian Gemini-200 (200MHz), Mercury-300 (300MHz) spectrometer, Bruker AVANCE AV300 (300MHz) and JNM-AL400 (400MHz) nuclear magnetic resonance apparatuses JEOL DATUM (JEOL DATUM LTD.) were used for the measurement. The following abbreviations are 20 used for showing the measurement results. s: singlet, d: doublet, dd: double doublet, ddd: triple doublet, dt: double triplet, t: triplet, q: quartet, dq: double quartet, m: multiplet, br: broad, brs: broad singlet, J: coupling constant, Hz: Hertz. 25 (0137]

Reference Example 1 tert-Butyl (2-oxoethyl) carbamate

To a mixed solution of tert-butyl (2-hydroxyethyl)carbamate (10.0 g) in dimethyl sulfoxide (50 mL) 30 and triethylamine (12.3 g) was added sulfur trioxide pyridine complex ¢15.0 g) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was further stirred at room temperature for 3 hr, 1 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The 35 separated aqueous layer was extracted again with ethyl acetate. 50 WO 2010/024451 PCT/JP2009/065279

The combined organic layers were washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=17:3—>13:7) to give 5 the title compound as'a pale-yellow oil (yield 6.50 g, 66%). ^-NMRtCDClaiezl^eOH^), 4.08 (2H, d, J=4.5Hz) , 5.19(lH,brs), 9.66<lH,s).

[0138]

Reference Example 2 jo Ethyl 4-[(tert-butoxycarbonyl)amino]-2,2-difluoro-3-{[(4-methylphenyl) sulfonyl]oxy}butanoate

Zinc powder (23.0 g) was washed with 0.1 mol/L hydrochloric acid, ethanol and diethyl ether, and dried under reduced pressure. Under an argon atmosphere, to a suspension 25 of washed zinc powder in tetrahydrofuran (300 mL) was added a solution of tert-butyl (2-oxoethyl)carbamate (35.0 g) in tetrahydrofuran (50 mL), ethyl bromodifluoroacetate (75.9 g) was gradually added dropwise under ice-cooling, and the mixture was stirred for 15 min. 1 mol/L Hydrochloric acid was 20 added to the reaction mixture, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium 25 sulfate and concentrated under.reduced pressure. The residue was dissolved in a mixed solution of tetrahydrofuran (30 mL) and pyridine (40 mL), triethylamine (19 mL), 4- dimethylaminopyridine (3.35 g) and 4-methylbenzenesulfonyl chloride (39.2 g) were added at room temperature, and the 30 mixture was stirred at for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, and washed twice with 1 mol/L hydrochloric acid. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed 35 with saturated aqueous sodium hydrogen carbonate solution, 51 WO 2010/024451 PCT/JP2009/065279 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=4:1) to give the title compound 5 as a pale-yellow oil (yield 44.8 g, 46%). ^-NMRfCDCla) 6: 1.33(3H,t,J=7.2Hz), 1.46(9H,s), 2.46<3H,s), 3.26-3.43(1H,m), 3.71<1H,brs), 4.28(2H,q,J=7.1Hz), 4.77(lH,brs), 5.08-5.24(lH,m), 7.35(2H,d,J=8.1Hz), 7.80(2H,d,J=8.1Hz). io [0139]

Reference Example 3 tert-Butyl 3,3-difluoro-4-{[(4-methylphenyl)sulfonyl]oxy}-2-oxopyrrolidine-l-carboxylate

To a solution of ethyl 4-[(tert-butoxycarbonyl)amino]-is 2,2-difluoro-3-{[(4-methylphenyl)sulfonyl]oxyIbutanoate (44.8 g) in ethyl acetate (50 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL), and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was azeotropically distilled 20 twice with toluene. The obtained mixture was dissolved in acetonitrile (20 mL), triethylamine (15.6 g) was added, and the mixture was stirred for 3 hr. Di-tert-butyl bicarbonate (33.6 g) and 4-dimethylaminopyridine (3.76 g) were added at room temperature and the mixture was stirred for 1 hr. The 25 reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, and washed with 1 mol/L hydrochloric acid. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated aqueous sodium hydrogen carbonate 30 solution, 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-2:1) to give the title compound as a pale-yellow oil (yield 32.0 g, 80%). 35 1H-NMR(CDCl3) δ: 1.55(9H,s), 2.48(3H,s), 3.81-3.91(lH,m), 4.09- 52 WO 2010/024451 PCT/JP2009/065279 4.18(lH,m), 4.94-5.06(lH,m), 7.40(2H,d,J=8.1Hz), 7.83(2H,d,J-8.1Hz).

[0140]

Reference Example 4 5 4, 4-Difluoro-5-(2-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-3-yl 4-methylbenzenesulfonate

To a solution of diisopropylamine (8.76 g) in tetrahydrofuran (230 mL) was added 1.6 mol/L n-butyllithium hexane solution (51 mL) at -78°C, and the mixture was stirred io for 1 hr. 2-Fluoropyridine (11.2 g) was added dropwise thereto, and the mixture was stirred for 2 hr. To the resultant pale-yellow suspension was slowly added dropwise a solution of tert-butyl 3,3-difluoro-4-{[(4-methylphenyl)sulfonyl]oxy)-2-oxopyrrolidine-l-carboxylate (22.6g) in tetrahydrofuran (50 is mL), and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was heated to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with water. The separated aqueous layer was extracted again with ethyl’ 20 acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained mixture was dissolved in dichloromethane (30 mL), trifluoroacetic acid (100 mL) was added dropwise under ice-cooling, and the mixture was stirred 25 for 4 hr while allowing the mixture to warm to room temperature. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and a saturated aqueous sodium hydrogen carbonate solution was added until the mixture became neutral. The separated aqueous layer was 30 extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:l—>3:1) to give the title compound as a 35 colorless solid (yield 10.9 g, 51%). 53 WO 2010/024451 PCT/JP2009/065279 xH-NMR(CDC13)6: 2.48(3H,s), 4.17-4.28(lH,m) , 4.42-4.54(lH,m), 5.06-5.13(lH,m), 7.31(1H, ddd,J=7.6,4.9,1.9Hz), 7.39(2H,d,J=7.9Hz), 7.85(2H,d,J=8.3Hz), 8.22-8.31(lH,m), 8.34- 8.39(lH,m). 5 [0141]

Reference Example 5 2- Fluoro-3-(3-fluoro-lH-pyrrol-2-yl)pyridine

To a solution of 4,4-difluoro-5-(2-fluoropyridin-3-yl)- 3,4-dihydro-2H-pyrrol-3-yl 4-methylbenzenesulfonate (18.0 g) jo in tetrahydrofuran (180 mL) was added sodium borohydride (3.68 g) under ice-cooling, methanol (90 mL) was further added, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water. The 15 separated aqueous layer was extracted again with ethyl acetate

Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ,4,4-difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate. To a suspension 20 of sodium hydride (9.74 g) in tetrahydrofuran (100 mL) was added dropwise a solution of 4,4-difluoro-5-(2-fluoropyridin- 3- yl)pyrrolidin-3-yl 4-methylbenzenesulfonate in tetrahydrofuran (100 mL) under ice-cooling, 15-crown-5 (32.2 g) was added, and the mixture was stirred for 3 hr. Saturated 25 aqueous ammonium chloride solution was added to the reaction mixture and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with 1 mol/L hydrochloric acid. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed 30 with saturated aqueous sodium hydrogen carbonate solution, 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—>3:1) to give the title compound as a 35 colorless solid (yield 6.35 g, 72%). 54 WO 2010/024451 PCT/JP2009/065279 ^-NMRiCDClaJd: 6.10 (1H, t, J=2.9Hz), 6.69(1H,dt,J=4.6,3.4Hz>, 7.20-7.30(lH,m) , 8. OO.(lH,dt, J»4.7,1.7Hz), 8.25(lH,ddd,J=10.3,7.8,1.9Hz), 8.69<lH,brs).

[0142] 5 Reference Example 6 2-Fluoro-3-{3-fluoro-l-[tris(1-methylethyl)silyl]-lH-pyrrol-2-yljpyridine

To a suspension of sodium hydride (3.32 g) in tetrahydrofuran (70 mL) was added dropwise a solution of 2- lo fluoro-3-(3-fluoro-lH-pyrrol-2-yl)pyridine (5.98 g) in tetrahydrofuran (30 mL) under ice-cooling and the mixture was stirred for 30 min. 15-Crown-5 (18.3 g) and tris(l-methylethyl)silyl trifluoromethanesulfonate (25.4 g) were added, and the mixture was stirred for 1 hr. The solvent was is evaporated to a half volume under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under 20 reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane—>hexane-ethyl acetate=19:1) to give the title compound as a pale-yellow oil (yield 10.9 g, 98%). 1H-NMR(CDCI3) δ: 1.04(18H,d,J=7.0Hz), 1.09-1.19(3H,m), 25 6.17(lH,dd,J=3.2,1.5Hz), 6.70(1H,dd,J=4.8,3.3Hz), 7.21(1H,ddd,J=7.3,4.9,1.7Hz), 7.78(1H,ddd,J=9.3,7.3,2.1Hz). [0143]

Reference Example 7 4-Fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrole-3-carbaldehyde 30' To a solution of N,N-dimethylformamide (717 mg) in dichloromethane (20 mL) was added oxalyl chloride (1.13 g) under ice-cooling under an argon atmosphere, and the mixture was stirred for 10 min. To the obtained suspension was added a solution of 2-fluoro-3-{3-fluoro-l-[tris(1-methylethyl)silyl]- 35 lH-pyrrol-2-ylIpyridine (1.50 g) in dichloromethane (5 mL) and 55 WO 2010/024451 PCT/JP2009/065279 the mixture was stirred under refluxing conditions for 10 hr.

The reaction mixture was cooled under ice-cooling, 1 mol/L aqueous sodium hydroxide solution (30 mL) was added and the mixture was stirred for 15 min. The solvent was evaporated to 5 a half volume under reduced pressure and the residue was partitioned by adding ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The io residual solid was washed with diisopropyl ether (30 mL) and filtered by suction to give the title compound as a colorless solid (yield 726 mg, 78%). 1H-NMR(CDCla) δ: 7.29-7.40 (2H,m), 8.11(1H, dt,J=4.8,1.6Hz), 8.29(1H,ddd,J=10.0,7.9,1.9Hz), 9.22(1H,brs), 9.90(lH,s). 15 [0144]

Reference Example 8 tert-Butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl]methylJmethylcarbamate

To a solution of 4-fluoro-5-(2-fluoropyridin-3-yl)-1H- 20 pyrrole-3-carbaldehyde (261 mg) in tetrahydrofuran (1 mL)- methanol (2 mL) was added 40% methylamine methanol solution (4 mL) at room temperature, and the mixture was stirred for 20 min. Sodium borohydride (142 mg) was added to the reaction mixture and the mixture was stirred for 1 hr. The reaction 25 mixture was concentrated under reduced pressure, water (4 mL) and ethyl acetate (4 mL) were added. Di-tert-butyl bicarbonate (410 mg) was added to the obtained mixture at room temperature and the mixture was stirred for 1 hr. The reaction mixture was separated between ethyl acetate and an aqueous layer, and the 30 separated aqueous layer was extracted again with ethyl acetate Combined organic layers were 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=9:1—*3:1) 35 to give the title compound as a colorless solid (yield 347 mg, 56 WO 2010/024451 PCT/JP2009/065279 86%) . 1H-NMR(CDCl3) δ: 1.49(9H,s), 2.88(3H,s), 4.31(2H,s), 6.46-6.94(lH,m), 7.15-7.32(lH,m), 8.00(1H,dt,J=4.7,1.7Hz), 8.23(1H,ddd,J=10.2,7.9,1.9Hz) , 8.66(1H,brs). 5 [0145]

Reference Example 9 2-(Benzylsulfanyl)-3-methylpyridine

To a suspension of sodium hydride (60% in oil, 1.44 g) in tetrahydrofuran (45 mL) was added dropwise phenylmethanethiol io (465 mg) at room temperature and the mixture was stirred for 15 min. 2-Bromo-3-methylpyridine (2.0 g) was added to the reaction mixture, and the mixture was stirred at 60°C for 1.5 hr. The reaction mixture was diluted with water, and concentrated under reduced pressure. The residual aqueous is layer was extracted twice with ethyl acetate. Combined organic layers were 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—*hexane-ethyl acetate=97:3) to give the title 20 compound as a gray oil (yield 1.79 g, 72%). 1H-NMR(CDCI3) δ: 2.23(3H,s),4.49(2H,s), 6.93(1H,dd,J=7.6,4.9Hz), 7.19-7.35(5H,m), 7.39-7.48(1H,m), 8.32(1H,dd,J=4.9,1.1Hz).

[0146]

Reference Example 10 25 3-Methylpyridine-2-sulfonyl chloride

To a solution of 2-(benzylsulfanyl)-3-methylpyridine (1.79 g) in acetic acid (16 mL)-water (8 mL) was added N-chlorosuccinimide (3.33 g) at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was 30 concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The 35 residue was purified by silica gel column chromatography 57 WO 2010/024451 PCT/JP2009/065279 (eluent: hexane-ethyl acetate=9:l—*3:2) to give the title compound as a crude pale-yellow oil (yield 153 mg). 1H-NMR (CDCI3) δ: 2.78(3H,s), 7.57(1H,dd,J=7.9,4.5Hz), 7.82(1H,ddd,J=7.7,1.5,0.8Hz), 8.61(1H,dd,J=4.5,1.1Hz). 5 [0147]

Reference Example 11 tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-lH-pyrrol-3-yl}methyl)methylcarbamate 10 To a suspension of sodium hydride (60% in oil, 20 mg) in tetrahydrofuran (2 mL) was added a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3- yl]methyl}methylcarbamate (161 mg), 15-crown-5 (110 mg), crude 3-methylpyridine-2-sulfonyl chloride (153 mg) in 15 tetrahydrofuran (1.5 mL) at room temperature, and the mixture was stirred at room temperature for 72 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with 20 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—*11: 9) to give the title compound as a colorless oil (yield 113 mg, 47%). 25 1H-NMR(CDCI3) δ: 1.47(9H,s), 2.43(3H,s), 2.90(3H,s), 4.32(2H,brs), 7.20(1H,ddd,J=7.4,5.0,1.7Hz), 7.29(1H,d,J-5.7Hz), 7.36(1H,dd,J=7.8,4.6Hz), 7.61(lH,dd,J«7.8,0.8Hz), 7.76-7.85(lH,m), 8.19(1H,ddd,J=4.9,2.0,1.0Hz), 8.29(lH,dd,J=4.5,0.9Hz). 30 [0148]

Reference Example 12 2-(Benzylsulfanyl)-4-methylpyridine

To a suspension of sodium hydride (60% in oil, 512 mg) in tetrahydrofuran (45 mL) was added dropwise phenylmethanethiol '35 (1.52 g) at room temperature, 2-bromo-4-methylpyridine (2.0 g) 58 WO 2010/024451 PCT/JP2009/065279 was added, and the mixture was stirred at 60°C for 72 hr. The reaction mixture was diluted .with water and extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and 5 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane—^hexane-ethyl acetate=24:1) to give the title compound as a brown oil (yield 1.40 g, 56%). ^-NMR (CDCI3) δ: 2.26(3H,s), 4.43(2H,s), 6.82(1H,d,J=5.1Hz), io 6.99(lH,s), 7.17-7.32(3H,m), 7.35-7.44(2H,m), 8.31(1H,d,J=5.1Hz).

[0149]

Reference Example 13 4-Methylpyridine-2-sulfonyl fluoride 15 To a solution of 2-(benzylsulfanyl)-4-methylpyridine (1.40 g) in acetic acid (10 mL)-water (5 mL) was added N-chlorosuccinimide (3.48 g) under ice-cooling, and the mixture was gradually warmed to room temperature and stirred for 4 hr. Potassium fluoride (379 mg) was added at room temperature and 20 the mixture was stirred for 18 hr. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The separated aqueous layer was extracted with ethyl acetate. Combined organic layers were washed with 25 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—>1:1) to give the title compound as a crude pale-yellow oil (yield 343 mg, 30%). 30 ^-NMRiCDClj) δ: 2.54 (3H, s) , 7.50 (1H, dt, J=4.9,0.7Hz) , 7.95(1H,d,J=0.8Hz), 8.69(1H, d,J=4.9Hz).

[0150]

Reference Example 14 tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4- 35 methylpyridin-2-yl)sulfonyl]-lH-pyrrol-3- 59 PCT/JP2009/065279 WO 2010/024451 yl}methyl)methylcarbamate

To a suspension (3 mL) of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl]methyl}methylcarbamate (323 5 mg), 15-crown-5 (330 mg) and 4-methylpyridine-2-sulfonyl fluoride (343 mg) at room temperature, and the mixture was stirred at room.temperature for 41 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate io Combined organic layers were 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 acetateM:1—>1:1) to give the title compound as a pale-yellow oil (yield 333 mg, is 70%) . 1H-NMR(CDClj) δ: 1.47(9H,s), 2.38(3H,s), 2.86(3H,s), 4.27(2H,brs), 7.27-7.34(3H,m), 7.36<lH,s>, 7.87(lH,ddd,J«9.2,7.5,1.9Hz), 8.26(1H,d,J=3.8Hz), 8.45(1H,d,J=4.9Hz). 20 [0151]

Reference Example 15 2-(Benzylsulfanyl)-5-fluoropyridine

To a suspension of sodium hydride (60% in oil, 440 mg) in tetrahydrofuran (40 mL) was added dropwise phenylmethanethiol 25 (1.37 g) at room temperature, 2-bromo-S-fluoropyridine (1.76 g) was added to the reaction mixture, and the mixture was stirred at 60°C for 5 hr. The reaction mixture was diluted with water and concentrated under reduced pressure. The residual aqueous layer was extracted twice with ethyl acetate. 30 Combined organic layers were 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—*hexane-ethyl acetate=97:3) to give the title compound as a crude brown oil 35 (yield 244 mg) . 60 PCT/JP2009/065279 WO 2010/024451 [0152]

Reference Example 16 5-Fluoropyridine-2-sulfonyl fluoride

To a solution of crude 2-(benzylsulfanyl)-5-5 fluoropyridine (244 mg) in acetic acid (3 mL)-water (1.5 mL) was added N-chlorosuccinimide (594 mg) under ice-cooling, and the mixture was gradually warmed to room temperature and stirred for 2 hr. Potassium fluoride (65 mg) was added at room temperature and the mixture was stirred for 1 hr. The reaction io mixture was concentrated under reduced pressure, diluted with water and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under is reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1—*3:1). to give the title compound as a crude colorless solid (yield 69 mg, 35%). lH-NMR(CDC13) δ: 7.75(1H,ddd,J=8.7,7.4,2.7Hz), 20 8.20(lH,dd,J=8.8,4.1Hz), 8.66(lH,d,J=2.8Hz).

[0153]

Reference Example 17 tert-Butyl ({4-fluoro-5-(2—fluoropyridin-3-yl)-1-[ (5-fluoropyridin-2-yl)sulfonyl]-lH-pyrrol-3- 25 yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 40 mg) in tetrahydrofuran (2.5 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl]methyl}methylcarbamate (162 mg), 15-crown-5 (220 mg) and 5-fluoropyridine-2-sulfonyl 30 fluoride ¢120 mg) at room temperature, and the mixture was stirred at room temperature for 28 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate Combined organic layers were washed with saturated brine,. 35 dried over anhydrous magnesium sulfate and concentrated under 61 WO 2010/024451 PCT/JP2009/065279 reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1—>7:3) to give the title compound as a pale-yellow oil (yield 69 mg, 29%) . 5 1H-NMR(CDtl3) 6: 1.48(9H,s), 2.88(3H,s), 4.27(2H,brs), 7.24-7.34(2H,m), 7.52(1H,ddd,J=8.7,7.5,2.8Hz), 7.68(lH,dd,J=8.7,4.1Hz) , 7.85(1H,ddd,J=9.2,7.4,2.0Hz), 8.27(lH,ddd,J=4.8,1.8,0.9Hz), 8.45(1H,d,J=2.6Hz).

[0154] io Reference Example 18 2-(Benzylsulfanyl)-4-methoxypyridine

To a solution of 2-chloro-4-methoxypyridine (786 mg) in toluene (10 mL) were added phenylmethanethiol ¢683 mg), N,N-diisopropylethylamine (1.56 g), is tris(dibenzylideneacetone)dipalladium(0) ¢202 mg) and 4,5-bis(diphenylphosphino)-9, 9-dimethylxanthene (256 mg), and the mixture was stirred at 80°C for 26 hr under an argon atmosphere. The reaction mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue 20 was purified by silica gel column chromatography (eluent: hexane—*hexane-ethyl acetate=19:l) to give the title compound as an orange oil (yield 454 mg, 38%). 1H-NMR(CDC13, δ: 3.79(3H,s), 4.43(2H,s), 6.57(lH,dd,J=5.9,2.5Hz), 6.68(1H,d,J=2.3Hz), 7.19-7.34<3H,m), 7.36-7.44(2H,m), 25 8.27(lH,d,J=5.7Hz).

[0155]

Reference Example 19 tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-lH-pyrrol-3- 30 yl}methyl)methylcarbamate

To a solution of 2-(benzylsulfanyl)-4-methoxypyridine ¢453 mg) in acetic acid (4 mL)-water (2 mL) was added N-chlorosuccinimide (1.10 g) under ice-cooling, gradually warmed to room temperature and the mixture was stirred for 5 hr. The 35 reaction mixture was concentrated under reduced pressure, 62 WO 2010/024451 PCT/JP2009/065279 diluted with water and extracted twice with ethyl acetate.

Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel 5 column chromatography (eluent: hexane-ethyl acetate=3:1—»1:1) to give crude 4-methoxypyridine-2-sulfonyl chloride as a pale-yellow oil. Then, to a suspension of sodium hydride (60% in oil, 30 mg) in tetrahydrofuran (2.5 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3- 10 yl]methyl)methylcarbamate (162 mg), 15-crown-5 (165 mg) and a solution of crude 4-methoxypyridine-2-sulfonyl chloride obtained above in tetrahydrofuran (2 mL) at room temperature, and the mixture was stirred for 18 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The is separated aqueous layer was extracted again with ethyl acetate Combined organic layers were 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=17:3—*1:1) 20 to give the title compound as a colorless oil (yield 96 mg, yield of 2 steps 9%). 1H-NMR(CDC13) S: 1.47(9H,s), 2.87(3H,s), 3.84(3H,s), 4.27(2H,brs), 6.94(1H,dd,J=5.6,2.4Hz), 7.07(1H,d,J=2.4Hz), 7.28(lH,dd,J-5.3,2.1Hz), 7.31<1H,d,J=5.7Hz), 25 7.87<lH,ddd, J=9.2,7.5,1.8Hz), 8.26 (1H, d,.J=4.7Hz), 8,39(1H,d,J=5.7Hz).

[0156]

Reference Example 20 3-(Benzylsulfanyl)-5-fluoropyridine 30 To a solution of 3-bromo-5-fluoropyridine (522 mg) in toluene (5 mL) were added phenylmethanethiol (370 mg), N,N-diisopropylethylamine (831 mg), tris(dibenzylideneacetone)dipalladium(O) (108 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (138 mg), and the 35 mixture was stirred under an argon atmosphere at 80°C for 2 hr. 63 WO 2010/024451 PCT/JP2009/065279

The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered through silica gel. The filtrate was concentrated under 5 reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane—>hexane-ethyl acetate-10:1) to give the title compound as an orange oil (yield 587 mg, 90%). ^-NMRfCDCla) δ: 4.13(2H,s), 7.23-7.33(6H,m), 8.25-8.26(1H,m), io 8.30-8.31(1H,m).

[0157]

Reference Example 21 5-Fluoropyridine-3-sulfonyl chloride

To a solution of 3-(benzylsulfanyl)-5-fluoropyridine (573 25 mg) in acetic acid (7.5 mL)-water (2.5 mL) was added N- chlorosuccinimide (1.40 g) at room temperature and the mixture was stirred for 1.5 hr. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted twice with ethyl acetate. Combined organic layers were washed with 20 saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was azeotropically distilled with toluene and purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1—> 7:3) to give the title compound as a colorless oil (yield 376 25 mg, 74%) . lH-NMR(CDC13) δ: 8.04(1H,ddd,J=7.0,2.7,2.0Hz), 8.85(1H,d,J-2.6Hz), 9.10(1H,dd,J=1.1,0.8Hz).

[0158]

Reference Example 22 30 tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 20 mg) in tetrahydrofuran (2 mL) were added tert-butyl {[4-fluoro-5-(2- 35 fluoropyridin-3-yl)-lH-pyrrol-3-yl]methyl}methylcarbamate (162 64 WO 2010/024451 PCT/JP2009/065279 mg), 15-crown-5 {132 mg) and a solution of 5-fluoropyridine-3- sulfonyl chloride (127 mg) in tetrahydrofuran {1 mL) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was diluted with water and extracted with 5 ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were 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- io ethyl acetate=9:1—>7:3) to give the title compound as a colorless oil (yield 224 mg, 93%). ^-NMRtCDClaJS: 1.48(9H,s), 2.88{3H,s), 4.27(2H,s), 7.28-7.36(2H,m), 7.38(1H,d,J=7.2Hz), 7.73-7.86(lH,m), 8.34(lH,d,J=4.2Hz), 8.46<lH,s), 8.69(1H,d,J=2.7Hz). is [0159]

Reference Example 23 3- (Benzylsulfanyl)-4-methylpyridine

To a solution of 3-bromo-4-methylpyridine (1.0 g) in toluene (12 mL) were added phenylmethanethiol (794 mg), N,N- 20 diisopropylethylamine ¢1.65 g), tris(dibenzylideneacetone)dipalladium(O) (213 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (269 mg), and the mixture was stirred under an argon atmosphere at 80°C for 1.5 hr. The reaction mixture was filtered through silica gel, and 25 the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1—>3:1~*1:1) to give the title compound as a yellow oil (yield 740 mg, 59%). 1H-NMR(CDCl3) δ: 2.27(3H,s), 4.07(2H,s), 7.06 (1H, d, J=4.9Hz), 30 7.14-7.35(5H,m), 8.30(1H,d,J=5.3Hz), 8.45(lH,s).

[0160]

Reference Example 24 4- Methylpyridine-3-sulfonyl chloride

To a solution of 3-(benzylsulfanyl)-4-methylpyridine (740 35 mg) in acetic acid (9 mL)-water (3 mL) was added N- 65 WO 2010/024451 PCT/JP2009/065279 chlorosuccinimide (1.84 g) at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted twice with ethyl acetate. Combined organic layers 5 were washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was azeotropically distilled with toluene and purified by silica gel column chromatography (eluent: hexane-ethyl io acetate=9: l—>3:1) to give the title compound as a crude colorless oil (yield 676 mg}. lH-NMR(CDCl3)5: 2.82 (3H,s), 7.34-7.44 (lH,m), 8.77(1H, d, J=4.9Hz) , 9.19(lH,s).

[0161] is Reference Example 25 tert-Butyl ((4-fluoro-5-(2-fluoropyridin-3-yl)-1-[ (4-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 24 mg) in 20 tetrahydrofuran (2 mL) were added tert-butyl {[4-fluoro-5-(2- fluoropyridin-3-yl)-lH-pyrrol-3-yl]methylimethylcarbamate (161 mg), 15-crown-5 (132 mg) and a solution of crude 4-methylpyridine-3-sulfonyl chloride (125 mg) in tetrahydrofuran (1 mL) at room temperature, and the mixture was stirred for 1 25 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was 30 purified by silica gel column chromatography (eluent: hexane-ethyl acetate=17: 3—>1:1) to give the title compound as a pale-yellow oil (yield 127 mg, 53%). 1H-NMR(CDCI3) δ: 1.49(9H,s), 2.36(3H,s), 2.92(3H,s), 4.32(2H,s), 7.19(lH,d,J«5.1Hz), 7.23-7.31(lH,m), 7.41(lH,brs), 35 7.82(1H,dt,J=8.3,1.9Hz), 8.18-8.26(2H,m), 8.58(1H,d,J=5.1Hz). 66 WO 2010/024451 PCT/JP2009/065279 [0162]

Reference Example 26 3-(Benzylsulfanyl)-5-methylpyridine

To a solution of 3-bromo-5-methylpyridine [888 mg) in 5 toluene (10 mL) were added phenylmethanethiol (705 mg)t N,N- diisopropylethylamine (1.47 g), tris(dibenzylideneacetone)dipalladium(O)(189 mg) and 4,5-bis (diphenylphosphino)-9,9-dimethylxanthene (239 mg), and the mixture was stirred under an argon atmosphere at 80°C for 1.5 io hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=!19:1—>17:3) to give the title compound as a yellow oil (yield 1.06 g, 95%). 15 xH-NMR(CDCl3) δ: 2.26(3H,d,J=0.8Hz), 4.09(2H,s), 7.20-7.33(5H,m), 7.37(lH,dt,J-2.1,0.8Hz), 8.25(1H,d,J=1.3Hz), 8.33(lH,d,J=2.1Hz).

[0163]

Reference Example 27 2o 5-Methylpyridine-3-sulfonyl chloride

To a solution of 3-(benzylsulfanyl)-5-methylpyridine ¢1.06 g) in acetic acid (15 mL)-water (5 mL) was added N-chlorosuccinimide (2.63 g) at room temperature and the mixture was stirred for 2 hr. The reaction mixture was concentrated 25 under reduced pressure, diluted with water and extracted twice with ethyl acetate. Combined organic layers were 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 30 acetate=19:1—»17:3) to give the title compound as a colorless oil (yield 700 mg, 74%). ^-NMRiCDClaJS: 2.52(3H,s), 7.96-8.22(lH,m), 8.78(1H,d,J=1.5Hz), 9.06(1H,d,J=2.3Hz).

[0164] 35 Reference Example 28 67 WO 2010/024451 PCT/JP2009/065279 tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5- methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3- ylJmethyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 24 mg) in 5 tetrahydrofuran (3 mL) were added tert-butyl {[4-fluoro-5-{2- fluoropyridin-3-yl)-lH-pyrrol-3-yl]methylJmethylcarbamate ¢323 mg), 15-crown-S (264 mg) and a solution of 4-methylpyridine-3-sulfonyl chloride (249 mg) in tetrahydrofuran (2 mL) at room temperature, and the mixture was stirred for 1 hr. The io reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified is by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1—*1:1) to give the title compound as a pale-yellow oil (yield 370 mg, 77%). ''H-NMR (CDC13) δ: 1.48(9H,s), 2.35 (3H, d, J=0.4Hz) , 2.86(3H,s), 4.26(2H,brs), 7.26(lH,s), 7.32(1H,ddd,J=7.3,5.2,1.5Hz), 20 7.38(lH,brs), 7.76-7.90(lH,m), 8.25-8.34(lH,m), 8.46(1H,d,J=2.1Hz), 8.63(1H,d,J=1.5Hz).

[0165]

Reference Example 29 tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6- 25 methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 31 mg) in tetrahydrofuran ¢3 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-ylJmethylJmethylcarbamate (100 30 mg), 15-crown-5 (170 mg), 6-methylpyridine-3-sulfonyl chloride hydrochloride (91 mg) at room temperature, and the mixture was stirred for 1.5 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic 35 layers were washed with saturated brine, dried over anhydrous 68 WO 2010/024451 PCT/JP2009/065279 magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=17:3~*1:1) to give the title compound as a pale-yellow oil (yield 123 mg, 83%). s XH-NMR(CDCI3) δ: 1.48(9H,s), 2.62(3H,s), 2.86(3H,s), 4.26(2H,s), 7.20(lH,d,J=8.0Hz), 7.27-7.34(2H,m), 7.51(1H,dd,J=8.0,1.9Hz), 7.76-7.86(lH,m), 8.27-8.36(lH,m), 8.50(1H,d,J=2.3Hz). (0166]

Reference Example 30 io 3-(Benzylsulfanyl)-2-methylpyridine

To a solution of 3-bromo-2-methylpyridine (1.0 g) in toluene (12 mL) were added phenylmethanethiol (794 mg), N,N-diisopropylethylamine (1.65 g), tris(dibenzylideneacetone)dipalladium(0) (213 mg) and 4,5- 15 bis(diphenylphosphino)-9,9-dimethylxanthene (269 mg), and the mixture was stirred under an argon atmosphere at 80°C for 4 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 20 hexane-ethyl acetate=9:1—>3:1) to give the title compound as a yellow solid (yield 742 mg, 59%). 1H-NMR(CDCI3) δ: 2.56(3H,s), 4.08 (2H,s), 7.03(1H,dd,J=7.6,5.0Hz), 7.21-7.34(5H,m), 7.48(1H,dd,J=7.8,1.6Hz), 8.30 (1H, dd, J=4.8,1.6Hz) . 25 [0167]

Reference Example 31 2-Methylpyridine-3-sulfonyl chloride

To a solution of 3-(benzylsulfanyl)-2-methylpyridine (731 mg) in acetic acid (9 mL)-water (3 mL) was added N- 30 chlorosuccinimide (1.81 g) at room temperature and the mixture was stirred for 4 hr. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and 35 concentrated under reduced pressure. The residue was purified 69 WO 2010/024451 PCT/JP2009/065279 by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1—»7:3) to give the title compound as a colorless oil (yield 175 mg, 27%). ^-NMRiCDClsJd: 3.03(3H,s), 7.40 (1H, dd, J=8.1,4.7Hz) , 5 8.33(lH,dd,J»8.1,1.7Hz), 8.80(1H,dd,J=4.7,1.7Hz).

[0168]

Reference Example 32 tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3- 10 yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 34 mg) in tetrahydrofuran (2 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl]methylimethylcarbamate (226 mg), 15-crown-5 (185 mg) and a solution of 2-methylpyridine-3- 15 sulfonyl chloride (174 mg) in tetrahydrofuran (1 mL) at room temperature, and the mixture was stirred for 18 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with 20 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=17:3—>1:1) to give the title compound as a yellow oil (yield 288 mg, 86%) . 25 1H-NMR(CDCI3) δ: 1.49(9H,s), 2.61(3H,s), 2.92(3H,s), 4.32(2H,s), 7.03(lH,dd,J=8.1,4.7Hz), 7.21-7.26(1H,m), 7.34(1H,dd,J-8.1,1.7Hz), 7.42(lH,brs), 7.79 (lH,ddd, J«9.-2, 7.3,2.1Hz), 8.19-8.26(1H,m) , 8.63(1H,dd,J=4.9,1.5Hz). 30 [0169]

Reference Example 33 2-(Benzylsulfanyl)-5-methoxypyridine

To a solution of 2-bromo-5-methoxypyridine (1.13 g) in toluene (15 mL) were added phenylmethanethiol (820 mg), N,N- 35 diisopropylethylamine (1.71 gf, 70 WO 2010/024451 PCT/JP2009/065279 tris(dibenzylideneacetone)dipalladium(O) (220 mg) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (278 mg), and the' mixture was stirred under an argon atmosphere at 80°C for 3 hr.

The reaction mixture was filtered through silica gel, and the 5 filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=49:1—>19:1) to give the title compound as a yellow oil (yield 1.47 g, quantitative). 1H-NMR(CDCI3) δ: 3.83(3H,s), 4.37(2H,s), 6.99-7.10(2H,m), 7.19-10 7.31(3H,m), 7.33-7.40<2H,m), 8.21(1H,dd,J=2.6,0.9Hz).

[0170]

Reference Example 34 5-Methoxypyridine-2-sulfonyl chloride

To a solution of 2-(benzylsulfanyl)-5-methoxypyridine 15 (1.47 g) in acetic acid (9 mL)-water (3 mL) was added N- chlorosuccinimide (3.20 g) at room temperature and the mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted twice with ethyl acetate. Combined organic layers were washed with 20 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—*17 : 3) to give the title compound as a colorless solid (yield 984 mg, 79%). 25 ^-NMRiCDClj) δ: 4.00(3H,s), 7.38 (1H, dd, J-8.9,2.8Hz) , 8.08(lH,d,J-8.7HZ), 8.43(1H,d,J=2.8Hz).

[0171]

Reference Example 35 tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5- 30 methoxypyridin-2-yl)sulfonyl]-lH-pyrrol-3-yl}methyl)methylcarbamate

To a suspension of sodium hydride (60% in oil, 168 mg) in tetrahydrofuran (10 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl]methyl}methylcarbamate (970 35 mg), 15-crown-5 (925 mg) and a solution of 5-methoxypyridine- 71 WO 2010/024451 PCT/JP2009/065279 2-sulfonyl chloride (984 mg) in tetrahydrofuran (15 mL) at room temperature, and the mixture was stirred for 30 min. The reaction mixture concentrated under reduced pressure to a half volume, diluted with water, and extracted with ethyl acetate. 5 The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were 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=17:3—>1:1) io to give the title compound as a yellow oil (yield 1.38 g, 93%) ^-NMR (CDCI3) δ: 1.47(9H,s), 2.87(3H,s), 3.91(3H,s), 4.26(2H,brs), 7.16(1H,dd,J=8.8,2.9Hz), 7.24-7.30(lH,m), 7.32(lH,d,J=5.5Hz), 7.52(1H,d,J=8.9Hz), 7.87(1H,ddd,J-9.2,7.4,2.1Hz), 8.23(1H,d,J=2.4Hz), 15 8.26(lH,ddd,J=4.9,1.9,0.9Hz) .

[0172]

Reference Example 36 5-Chloropyridin-3-yl trifluoromethanesulfonate

To a solution of 5-chloropyridin-3-ol (1.30 g) in 20 tetrahydrofuran (50 mL) were added triethylamine (1.21 g) and N-phenylbis(trifluoromethanesulfonimide) (3.93 g) at room temperature, and the mixture was stirred for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with 1 25 mol/L hydrochloric acid. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography 30 (eluent: hexane-ethyl acetate=99:1—*19:1) to give the title compound as a colorless oil (yield 1.73 g, 66%). 1H-NMR (CDCI3) δ: 7.69(lH,t,J=2.3Hz), 8 ..52 (1H, d, J=2.3Hz) , 8.64(lH,d,J=1.9Hz).

[0173] 35 Reference Example 37 72 WO 2010/024451 PCT/JP2009/065279 3- (Benzylsulfanyl) -5-chloropyridine

To a solution of 5-chloropyridin-3-yl trifluoromethanesulfonate (1.73 g) in toluene (15 mL) were added phenylmethanethiol (861 mg), N,N-diisopropylethylamine 5 (1.88 g), tris(dibenzylideneacetone)dipalladium(O) (121 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (153 mg), and the mixture was stirred under an argon atmosphere at 80°C for 3 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The io residue was purified by silica gel column chromatography (eluent: hexane—>hexane-ethyl acetate=19:1) to give the title compound as a yellow oil (yield 1.63 g, quantitative). XH-NMR(CDC13)5: 4.12(2H,s), 7.21-7.36(5H,m), 7.53<1H,t,J=2.1Hz), 8.36(2H,d,J-l.9Hz). 15 (0174]

Reference Example 38 5-Chloropyridine-3-sulfonyl chloride

To a solution of 3-(benzylsulfanyl)-5-chloropyridine (1.63 g) in acetic acid (9 mL)-water (3 mL) was added N- 20 chlorosuccinimide (3.53 g) at room temperature and the mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and 25 concentrated under reduced pressure. The residue was azeotropically distilled with toluene and purified by silica gel column chromatography (eluent: hexane-ethyl acetate=49:l—* 9:1) to give the title compound as a colorless oil (yield 1.26 ‘ g, 90%). 30 XH-NMR(CDC13) δ: 8.29(1H,t,J=2.2Hz), 8.91(1H,d,J=2.2Hz), 9.12(lH,d,J-l.9Hz).

[0175]

Reference Example 39 tert-Butyl ({1-[(5-chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2- 35 fluoropyridin-3-yl)-lH-pyrrol-3-yl)methyl)methylcarbamate 73 WO 2010/024451 PCT/JP2009/065279

To a suspension of sodium hydride <60% in oil, 52 mg) in tetrahydrofuran (3 mL) were added tert-butyl {[4-fluoro-5-(2- fluoropyridin-3-yl)-lH-pyrrol-3-yl]methyl}methylcarbamate (323 mg), 15-crown-5 (286 mg) and a solution of 5-chloropyridine-3- 5 sulfonyl chloride (318 mg) in tetrahydrofuran (2 mL) at room temperature, and the mixture was stirred for 20 min. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with io 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—*7:3) to give the title compound as a colorless oil (yield 391 mg, 78%). is 1H-NMR(CDC13)5: 1.48(9H,s), 2.88(3H,s), 4.27(2H,s), 7.26(lH,s), 7.33(lH,ddd,J-7.3,5.2,1.5Hz), 7.61(1H,t,J=2.1Hz), 7.80(1H,ddd,J=9.2,7.5,1.9Hz), 8.26-8.38(lH,m), 8.50(1H,d,J=1.9Hz), 8.76(1H,d,J=2.3Hz).

[0176] 20 Example 1 1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine fumarate

To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H- 25 pyrrol-3-yl]methyl)methylcarbamate (107 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) were added 4 mol/L hydrogen chloride-ethyl acetate solution ¢3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was 30 diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced 35 pressure. The residue was purified by basic silica gel column 74 WO 2010/024451 PCT/JP2009/065279 chromatography (eluent: hexane-ethyl acetate=4:l—>l:l) to give l-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2- yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine as a pale- yellow oil (yield 45 mg, 54%). A solution of the obtained 1- 5 {4-fluoro-S-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2- yl) sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (14 mg) in ethanol (2 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from io ethyl acetate-ethanol to give the title compound as a white solid (yield 51 mg, 86%) . ^-NMR (DMSO-dg) δ: 2.35(3H,s), 2.38(3H,s), 3.73(2H,s), 6.53(2H,s), 7.32-7.39(lH,m), 7.48(1H,d,J=5.7Hz), 7.63<1H,dd,J=7.8,4.4Hz), 7.74-7.83(lH,m), 7.93(1H,d,J-7.6Hz), is 8.27(1H,d,J=4.2Hz),8.41(1H,d,J=4.5Hz),3H not detected.

[0177]

Example 2 1—{4—Fluoro—5—(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-lH-pyrrol-3-yl)-N-methylmethanamine 20 hydrochloride

To a solution of tert-butyl {{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (333 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen 25 chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 191 mg, 66%). 30 1H-NMR(DMSO-dg) δ: 2.37(3H,s), 2.56(3H,s), 4.05(2H,s), 7.45(1H,ddd,J=7.3,5.0,1.7Hz), 7.54(lH,s), 7.59-7.66(lH,m), 7.77-7.90(2H,m), 8.33-8.40(lH,m), 8.55(1H,d,J=4.9Hz), 9.11(2H,brs).

[0178] 35 Example 3 75 WO 2010/024451 PCT/JP2009/065279 1-{4-Fluoro-5-(2—fluoropyridin-3-yl)-1-[(5-fluoropyridin-2- yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine hydrochloride

To a solution of tert-butyl {{4-fluoro-5-(2- j fluoropyridin-3-yl)-1-[(5-fluoropyridin-2-yl) sulfonyl]-1H- pyrrol-3-yl}methyl)inethylcarbamate (69 mg) in ethyl acetate (1.5 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture io was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 31 mg, 51%). ^-NMRiDMSO-deja: 2.58(3H,s), 4.07(2H,s), 7.41-7.49(lH,m), 7.80(lH,d,J=5.5Hz), 7.82-7.91(2H,m), 8.05(1H,dt,J=8.6,2.8Hz), is 8.36(lH,ddd,J=4.9,1.9,0.9Hz), 8.78(1H, d,J=2.8Hz), 8.97(2H,brs) [0179]

Example 4 1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine 20 hydrochloride

To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (94 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride- 25 ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 65 mg, 79%). 30 1H-NMR(DMSO-dg) δ: 2.57(3H,s), 3.87(3H,s), 4.06(2H,s), 7.17(lH,d,J=2.3Hz), 7.33(1H,dd,J=5.7,2.7Hz), 7.46(1H,ddd,J=6.9,5.2,1.5Hz), 7.80(1H,d,J=5.7Hz), 7.89(1H,ddd,J=9.3,7.6,1.7Hz), 8.30-8.39(lH,m), 8.51 (lH,d,J-5.7Hz), 9.01(2H,brs). 35 [0180] 76 WO 2010/024451 PCT/JP2009/065279

Example 5 1-{4-Fluoro-5-< 2—fluoropyridin-3-yl)-1-[(5-fluoropyridin-3- yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine hydrochloride j To a solution of tert-butyl ({4-fluoro-5-(2- fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (224 mg) in ethyl acetate (2 mL) and 2-propanol ¢1 mL) was added 4N hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at io room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 127 mg, 65%). 1H-NMR(DMSO-d6)5: 2.58(3H,s), 4.05(2H,s), 7.46-7.55(lH,m), 15 7.87-7.97(2H,m), 8.03(1H,dt,J=7.6,2.3Hz), 8.42(1H,d,J=4.2Hz), 8.49(lH,s), 9.04(1H,d,J=2.3Hz), 9.09(2H,brs).

[0181]

Example 6 1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3- 20 yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine fumarate To a solution of tert-butyl ({4-fluoro-5-(2- fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl]methyl)methylcarbamate (127 mg) in ethyl acetate (2 mL) and 2-propanol (0.5 mL) was added 4N hydrogen chloride- 25 ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated 30 aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl)-N-

35 methylmethanamine as a pale-yellow oil (yield 97 mg, 97%). A 77 WO 2010/024451 PCT/JP2009/065279 solution of the obtained 1-(4-fluoro-5-(2-fluoropyridin-3-yl)- 1-[(4-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}-N- methylmethanamine in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (30 mg) in ethanol (2 mL) and 5 concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a white solid (yield 103 mg, 81%). 1H-NMR(DMSO-dg) δ: 2.33(3H,s), 2.40(3H,s),3.76(2H,s), 6.53(2H,s), 7.43(lH,ddd,J=7.3,5.1,1.8Hz), 7.52(lH,d,J=5.1Hz), io 7.72(1H,d,J=5.7Hz), 7.85(1H,ddd,J=9.5,7.4,1.9Hz), 8.14(lH,s), 8.32(1H,ddd,J=4.9,1.9,0.9Hz), 8.70(1H,d,J=5.1Hz), 3H not detected.

[0182]

Example 7 u l-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine fumarate

To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-ylJmethyl)methylcarbamate (370 mg) in ethyl acetate 20 (2 mL) and 2-propanol (1 mL) was added 4N hydrogen chloride- ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate 25 solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1-(4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5- 30 methylpyridin-3-yl) sulfonyl]-lH-pyrrol-3-yl)-N- methylmethanamine as a pale-yellow oil (yield 256 mg, 88%). A solution of the obtained 1-(4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl)-N-methylmethanamine in ethyl acetate (2 mL) was added dropwise 35 to a solution of fumaric acid (78 mg) in ethanol (2 mL) and 78 WO 2010/024451 PCT/JP2009/065279 concentrated, under reduced pressure. The residue was recrystallized from ethanol-water to give the title compound as a white solid (yield 288 mg, 87%). ^-NMRfDMSO-dg) δ: 2.33{3H,s), 2.35(3H,s), 3.70(2H,s), 5 6.54(2H,s), 7.50(lH,ddd,J=7.3,5.1,1.9Hz), 7.63-7.71(2H,m), 7.90(lH,ddd,J=9.6,7.5,2.0Hz), 8.36-8.41(lH,m), 8.42(lH,d,J=2.3Hz), 8.76(1H,d,J«1.3Hz), 3H not detected.

[0183]

Example 8 io l-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl) sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine 0.5 fumarate

To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl)methyl)methylcarbamate (123 mg) in ethyl acetate 15 (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate 20 solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column 25 chromatography (eluent: hexane-ethyl acetate^l:1) to give 1-(4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl)-N-methylmethanamine as a colorless oil (yield 88 mg, 91%). A solution of the obtained 1 {4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3- 30 yl) sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (27 mg) in ethanol (2 mL) and concentrated under reduced pressure. The residue was recrystallized from ethanol-water to give the title compound as a white solid (yield 78 mg, 77%). 55 ^-NMRiDMSO-ddS: 2.30(3H,s), 2.56(3H,s), 3.61(2H,s), 79 WO 2010/024451 PCT/JP2009/065279 6.51(lH,s), 7.45-7.53(2H,m) , 7.60(1H,d,J=5.7Hz), 7.79(1H,dd,J=8.3,2.3Hz), 7.91(1H,ddd,J=9.6,7.5,1.9Hz), 8.35- 8.40(lH,m), 8.48(lH,d,J=2.3Hz), 2H not detected.

[0184] 5 Example 9 1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine fumarate

To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-1H- io pyrrol-3-yl]methyl)methylcarbamate (288 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was is diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced 20 pressure to give 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine as a colorless oil (yield 220 mg, 97%). A solution of the obtained 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1- [ (2-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl]-N- 25 methylmethanamine in ethyl acetate (3 mL) was added dropwise to a solution of fumaric acid (67 mg) in ethanol (3 mL) and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a white solid (yield 253 mg, 88%). 30 1H-NMR(DMSO-d6)5: 2.41(3H,s), 2.49(3H,s), 3.77(2H,s), 6.53(2H,s), 7.31(1H, dd,J=8.1,4.7Hz), 7.42(1H,ddd,J=7.2,5.1,1.7Hz), 7.47(1H,dd,J=8.3,1.5Hz) , 7.71(lH,d,J=5.7Hz), 7.84(1H,ddd,J=9.6,7.5,1.9Hz), 8.28-8.34(lH,m), 8.73(1H,dd,J=4.7,1.7Hz), 3H not detected. 35 [0185] 80 WO 2010/024451 PCT/JP2009/065279

Example 10 l-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methoxypyridin-2-yl) sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine hydrochloride 5 To a solution of tert-butyl ({4-fluoro-5-(2- fluoropyridin-3-yl)-1-[(5-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (1.38 g) in ethyl acetate (6 mL) and 2-propanol (3 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (9 mL), and the mixture was jo stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol-water to give the title compound as a white solid (yield 1.06 g, 88%). ^-NMRCDMSO-deJS: 2.54{3H,s), 3.91(3H,s), 4.03(2H,s), 7.38- 15 7.46(lH,m), 7.51-7.58(lH,m), 7.62-7.70(lH,m), 7.75-7.87(2H,m), 8.33(1H,dt,J=4.7,0.8Hz), 8.36(1H,d,J=3.0Hz), 9.20(2H,brs). [0186]

Example 11 1-{1- [ (5-Chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2- 20 fluoropyridin-3-yl)-lH-pyrrol-3-yl}-N-methylmethanamine hydrochloride

To a solution of tert-butyl ({1-[(5-chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl)methyl)methylcarbamate (391 mg) in ethyl acetate (2 mL) and 25 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1.5 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 30 (yield 298 mg, 95%). 1H-NMR(DMSO-dg) δ: 2.57(3H,s), 4.05(2H,s), 7.52(1H,ddd,J=7.3, 5.1,1.9Hz), 7.93(1H, ddd,J=9.6,7.5,2.0Hz), 8.01 (1H, d, J=5.5Hz) , 8.11(1H,t,J=2.2Hz), 8.43(lH,ddd,J=4.9,1.8,0.8Hz), 8.57(1H,d,J=2.1Hz), 35 9.05(1H,d,J=2.1Hz), 9.33(2H,brs). 81 WO 2010/024451 PCT/JP2009/065279 [0187]

Example 12 1-{4-Fluoro—1—[(5-fluoro-6-methylpyridin-2-yl)sulfonyl]-5-(2- fluoropyridin-3-yl)-lH-pyrrol-3-yl}-N-methylmethanamine 5 The compound is synthesized in the same manner as in

Reference Example 15, Reference Example 16, Reference Example 17 and Example 3 and using 6-bromo-3-fluoro-2-methylpyridine. [0188]

Example 13 10 l-{4-Fluoro~l-[(5-fluoro-4-methylpyridin-2-yl)sulfonyl]-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl}-N-methylmethanamine

The compound is synthesized in the same manner as in

Reference Example 15, Reference Example 16, Reference Example 17 and Example 3 and using 2-bromo-5-fluoro-4-methylpyridine. u [0189]

Example 14 1-{4-Fluoro-l-[(5-fluoro-4-methoxypyridin-2-yl) sulfonyl]-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl}-N-methylmethanamine tert-Butyl group is removed from 4-tert-butoxy-2,5-20 difluoropyridine, and the resulting compound is methylated to give 2,5-difluoro-4-methoxypyridine, which is then subjected to synthesis in the same manner as in Reference Example 15, Reference Example 16, Reference Example 17 and Example 3.

[0190] 25 Example 15 1—{4-Fluoro-S-(2-fluoropyridin-3-yl)-1-[{5-methoxypyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine

The compound is synthesized in the same manner as in

Reference Example 20, Reference Example 21, Reference Example 30 22 and Example 5 and using 3-bromo-5-methoxypyridine.

[0191]

Example 16 1-[4-Fluoro—1-[(5-fluoro-6-methylpyridin-3-yl)sulfonyl]-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl}-N-methylmethanamine 35 5-Chloro-3-fluoro-2-methylpyridine is synthesized from 5- 82 WO 2010/024451 PCT/JP2009/065279 chloro-3-fluoro-2-iodopyridine by a boronic acid coupling reaction and the resulting compound is subjected to synthesis in the same manner as in Reference Example 20, Reference

Example 21, Reference Example 22 and Example 5. 5 [0192]

Example 17 1-{1- [ (4,6-Dimethylpyridin-2-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl}-N-methylmethanamine

The compound is synthesized in the same manner as in io Reference Example 15, Reference Example 16, Reference Example 17 and Example 3 and using 2-bromo-4,6-dimethylpyridine.

[0193]

Example 18 1— {1—[(5-Chloropyridin-2-yl)sulfonyl]-4-fluoro-5-(2- 15 fluoropyridin-3-yl)-lH-pyrrol-3-yl}-N-methylmethanamine

The compound is synthesized in the same manner as in

Reference Example 17 and Example 3 and using 5-chloropyridine 2- sulfonyl chloride.

[0194] 20 Example 19 1-{1-[(5,6-Dimethylpyridin-2-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl}-N-methylmethanamine

The compound is synthesized in the same manner as in Reference Example 15, Reference Example 16, Reference Example 25 17 and Example 3 and using 6-bromo-2,3-dimethylpyridine.

[0195]

Example 20 1-{1-[(4,5-Dimethylpyridin-2-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-lH-pyrrol-3-yl]-N-methylmethanamine 30 The compound is synthesized in the same manner as in

Reference Example 15, Reference Example 16, Reference Example 17 and Example 3 and using 2-bromo-4,5-dimethylpyridine.

[0196]

Example 21 35 1-[4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2- 83 211335/2 yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine 1—{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin- 2- yl) sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine hydrochloride (751 mg) was dissolved in saturated aqueous 5 sodium hydrogen carbonate, and extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 647 mg, 95%). io 1H-NMR(CDCI3) δ: 2.38(3H,s), 2.45(3H,s), 3.64(2H,s), 7.23-7.30(2H,m), 7.33(1H,d,J-5.7Hz), 7.36(lH,s), 7.88(1H,ddd,J=9.3,7.4,1.9Hz), 8.22-8.29 <lH,m), 8.45(1H,d,J=4.5Hz), 1H not detected.

[0197] 15 Example 22 1-f 4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine 1- {4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin- 3- yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine 20 hydrochloride (780 mg) was dissolved in saturated aqueous sodium hydrogen carbonate, and the mixture was extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified 25 by basic silica gel column chromatography (eluent: hexane-ethyl acetate=3:1_>3:7) to give the title compound as a pale-yellow oil (yield 619 mg, 87%). ^-NMR (CDC13) δ : 2.46(3H,s), 3.65(2H,s), 7.28-7.36 (2H, m) , 7.41 (lH,dt,J=7.3,2.2Hz), 7.80(1H,ddd, J=9.2,7.4,2.0Hz), 8.28- 30 8.39(lH,m), 8.48(lH,s), 8.68 (1H, d, J=2.6Hz) , 1H not detected. [0198]

Example 23 l-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-lH-pyrrol-3-yl)-N-methylmethanamine fumarate 35 To a solution of fumaric acid (58 mg) in ethanol (2 mL) 84 WO 2010/024451 PCT/JP2009/065279 was added a solution of l-(4-fluoro-5~(2-fluoropyridin-3-yl) -1-t(4-methylpyridin-2-yl)sulfonyl]-lH-pyrrol-3-yl}-N- methylmethanamine (189 mg) in ethyl acetate (2 ml), and the mixture was concentrated under reduced pressure. The residue' 5 was recrystallized from ethanol to give the title compound as a white solid (yield 224 mg, 91%) . ^-NMR (DMSO-dg) δ: 2.35-2.40(6H,m), 3.73(2H,s), 6.53<2H,s), 7.44(lH,ddd,J=7.3,5.1,1.8Hz), 7.49-7.55(2H,m), 7.59(1H, d, J=4.9Hz), 7.86(1H,ddd,J=9.5,7.4,1.9Hz), 8.27- io 8.39(lH,m), 8.54 (1H, d, J=4.9Hz), 3H not detected.

[0199]

Example 24 1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl) sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine succinate is To a solution of succinic acid (59 mg) in ethanol (2 mL) was added a solution of 1-(4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-lH-pyrrol-3-yl)-N-methylmethanamine (189 mg) in ethyl acetate (2 mL) and the mixture was concentrated under reduced pressure. The residue 20 was recrystallized from ethanol-water to give the title compound as a white solid (yield 232 mg, 93%). 1H-NMR(DMSO-dg) δ: 2.34(3H,s), 2.36(4H,s), 2.37(3H,s), 3.66(2H,s), 7.39-7.49(2H,m), 7.52(lH,s), 7.55-7.63(lH,m), 7.86(1H, ddd,J=9.5,7.4,1.9Hz), 8.34(1H,ddd,J=4.9,1.9,0.9Hz), 25 8.54(1H,d,J=4.9Hz), 3H not detected.

[0200]

Example 25 1-(4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine 0.5 fumarate 30 To a solution of fumaric acid (36 mg) in ethanol (2 mL) was added a solution of 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl)-N-methylmethanamine (120 mg) in ethyl acetate (2 mL) and the mixture was concentrated under reduced pressure. The residue 35 was recrystallized from ethanol to give the title compound as 85 211335/2 a white solid (yield 113 mg, 82%). ^-NMR (DMSO-dg) δ: 2.32(3H,s), 3.63{2H,s), 6.52(lH,s), 7.50(1H, ddd,J=7.3, 5.1,1.9Hz), 7.67(1H,d,J=5.7Hz), 7.94(1H,ddd,J=9.6,7.5,2.0Hz), 7.98-8.05(1H,m), 8.31-8.42(lH,m) , 5 8.48(lH,s), 9.00(1H,d,J=2.8Hz), 2H not detected.

[0201]

Example 26 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl]-N-methylmethanamine succinate io A solution of succinic acid (46 mg) in ethanol (4 mL) was added to l-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine (150 mg), and the mixture was concentrated under reduced pressure. The residue was recrystallized from is ethanol to give the title compound as a white solid (yield 167 mg, 85%). ^-NMR (DMSO-dg) δ : 2.33(3H,s), 2.38(4H,s), 3.64(2H,s), 7.50(1H,ddd,J-7.2,5.0,1.9Hz), 7.66(1H, d, J=5.7Hz), 7.94(lH,ddd,J=9.6,7.5,2.0Hz), 7.98-8.03(1H,m), 8.34-8.42(lH,m), 20 8.44-8.53(lH,m), 9.01(1H,d,J=2.6Hz), 3H not detected.

[0202]

Example 27 1-{4-Fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl]-N-methylmethanamine L-tartrate 25 A solution of L-tartaric acid (59 mg) in ethanol (4 mL) was added to l-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine (150 mg), and the mixture was concentrated under reduced pressure. The residue was recrystallized from 30 ethanol to give the title compound as a white solid (yield 184 mg, 88%). 1H-NMR (DMSO-dg) δ: 2.44(3H,s), 3.81(2H,s), 4.00(2H,s), 7.51(1H, ddd,J=7.3,5.2,1.9Hz), 7.75 (1H,d,J=5.7Hz), 7.93(lH,ddd,J=9.5,7.4,1.9Hz), 8.00(1H, dt,J=7.8,2.3Hz), 8.38- 35 8.43 (lH,m), 8.49(lH,s), 9.02(1H,d,J=2.6Hz), 5H not detected. 86 WO 2010/024451 PCT/JP2009/065279 10203]

The structures of the compounds described in Reference Examples are shown in Tables 1-2.

[0204] 5 Table 1

Ref .Ex.No. R8 Rb

Ref.Ex.No. Ra

Rb 5 H MeJ*e H 28 mZ „Me ‘^"'Boc 6 μ/ Jl H 29 Uo v CH,NC* 1 Boc 7 H CHO 32 MC CH><\ 8 H ^Me ch’n'b== 35 11 CH Me Me 39 £><= cr 14 p-sgo Me 17 19 MeO 22 p CH^'c 25 CH° Me [0205] 87 WO 2010/024451

Table 2 PCT/JP2009/065279

Structural formulas of Reference.Examples 1-4 f oTs F ( ( / N ΟΤβ 1 Boc . 1 2 3 . 4

Other structural formulas of Reference

Examples 9-39

27 30

24 26

Cl o=s=o

38 [0206]

The structures of the compounds described in Examples are 5 shown in Table 3.

[0207] 88 WO 2010/024451

Table 3 PCT/JP2009/065279

[0208] 5 Experimental Example 1

Proton potassium - adenosine triphosphatase (H+,K+-ATPase) inhibitory activity test 69 WO 2010/024451 PCT/JP2009/065279

According to the method [Biochim. Biophys. Acta, 728, 31 ¢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, 5 immersed in 3 mol/L brine, and the surface of the mucous membrane was wiped with a paper towel. The gastric mucous 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 io (Kinematics). The obtained homogenate was centrifuged at 20,000xg for 30 min and the supernatant was centrifuged at 100,000xg 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 is 100,000xg for 5 hr. The fraction containing the interface between the both layers was recovered, and centrifugally washed with 0.25 mol/L saccharose solution. The obtained microsomal fraction was used as a proton, potassium -adenosine triphosphatase standard product. 20 [0209]

To 40 pL of a 50 mmol/L HEPES-tris buffer (5 mmol/L magnesium chloride, 10 mmol/L potassium chloride, 10 pmol/L valinomycin, pH=6.5) containing 2.5 pg/mL (based on the protein concentration) of the enzyme standard product was added a test 25 compound (5 pL) dissolved in a 10% aqueous dimethyl sulfoxide solution, and the mixture was incubated at 37°C for 30 min.

The enzyme reaction was started by adding 5 pL of a 2 mmol/L adenosine triphosphate tris salt solution (50 mmol/L HEPES-tris buffer (5 mmol/L magnesium chloride, pH 6.5)). The enzyme 30 reaction was carried out at 37°C for 20 min, and 15 pL of a malachite green solution (0.12% malachite green solution in sulfuric acid ¢2.5 mol/L), 7.5% ammonium molybdate and 11%

Tween 20 were mixed at a ratio of 100:25:2) was added to quench the reaction. After allowing to stand at room 35 temperature for 15 min, the resulting reaction product of 90 WO 2010/024451 PCT/JP2009/065279 inorganic phosphorus with malachite green was colorimetrically determined at a wavelength of 620 nm. In addition, the amount of the inorganic phosphoric acid in the reaction solution free of potassium chloride was measured in the same manner, which 5 was subtracted from the inorganic phosphoric acid amount in the presence of potassium chloride to determine the proton, potassium - adenosine triphosphatase activity. The inhibitory rate (%) was determined from the activity value of the control and the activity values of various concentrations of the test io compound, and the 50% inhibitory concentration (ICs0) of the proton, potassium - adenosine triphosphatase was determined.

The results are shown in Table 4.

[0210]

Experimental Example 2 is The pKa values were calculated using Physchem Batch {Ver. 10) (Advanced Chemistry Development, Inc.). The results are shown in Table 4.

[0211]

Experimental Example 3 20 ATP content test

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), 25 2 mmol/L L-glutamine (Invitrogen), 50 IU/mL penicillin (Invitrogen) and 50 pg/mL streptomycin (Invitrogen) at 5% CO2, 37°C. 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 30 50 pg/mL streptomycin to a final concentration of DMSO of 0.1%. HepG2 (2xl04 cells/well) was cultured on a 96 well white plate (Costar) with the test reagent at 5% CO2, 37°C. After culture for one day, the intracellular ATP content was measured using ATPLite™ (PerkinElmer Life Sciences). The results are shown 35 in Table 4 (n£3, average value ± SD) as a relative value (%) to 91 WO 2010/024451 PCT/JP2009/065279 control (without addition of drug).

[0212]

Experimental Example 4

Caspase-3/7 activity test 5 The Caspase-3/7 activity in the cells cultured for one day by a method similar to that in Experimental Example 3 was measured using Caspase-Gio 3/7 Assay (Promega). The results are shown in Table 4 (n£3, average value ±SD) as relative activity (%) of each reagent based on the maximum value of io Caspase-3/7 activity when exposed to Staurosporine (100%), and the activity without addition of a test reagent (0%).

[0213]

Experimental Example 5

Measurement of perfusate pH in anesthetized rat stomach is reperfusion model

Jcl:SD male rats (8-week-old) were fasted for about 24 hr and used for the experiment. The test compounds were dissolved in a DMAA:PEG400-1:1 solution to the dose of 1 mL/kg. Under anesthesia with urethane (1.2 g/kg, i.p.), cannulas were 20 inserted from the duodenum and the forestomach into the stomach, the esophagus was ligated and the stomach was reperfused with physiological saline (0.5 mL/min). The perfusate was subjected to a continuous pH measurement using trace flow type glass electrodes (6961-15C and 2461A-15T, 25 HORIBA). Histamine dihydrochloride (8 mg/kg/h) was continuously administered for 1 hr or longer by intravenous infusion. After the pH was stabilized, the test compound was intravenously administered. The pH of the perfusate was measured until 5 hours after administration of the test 30 compound. The results are shown in Figs. 1, 2 and 3.

[0214] 92 WO 2010/024451

Table 4 PCT/JP2009/065279

Example No. H+/K+-ATPase inhibitory activity (IC50, nM) pKa value (calculated) ATP content (%, 100 μΜ) Caspase-3/7 activity (%, 100 pM) 2 100 7.84 85.5 -1.1 3 100 7.77 86.5 -0.5 4 140 7.79 84.5 -0.6 5 200 7.73 88.9 0.3 8 180 7.81 76.7 2.4 10 280 7.79 80.0 0.9 23 83 7.84 - - 24 140 7.84 - - 25 200 7.73 - - 26 130 7.73 - - 27 . 160 7.73 - - [0215]

From the results of Table 4, it is clear that compound 5 (I) of the present invention has a superior H+/K+-ATPase inhibitory activity and a low pKa value, as well as extremely low cytotoxicity even when used at a high concentration. In addition, from the results of Figs. 1, 2 and 3, it is clear that compound (I) has a moderate duration of action. 10 INDUSTRIAL APPLICABILITY [0216]

Compound (I) of the present invention shows a superior proton pump inhibitory effect. Conventional proton pump inhibitors such as omeprazole, lansoprazole and the like are 15 converted to active forms in an acidic environment of gastric parietal cells and form a covalent bond with a cysteine residue of H+/K+-ATPase, and irreversibly inhibit the enzyme activity. In contrast, compound ¢1) inhibits proton pump (H+/K+-ATPase) activity in a reversible and K+ competitive 20 manner, and consequently suppresses acid secretion. Therefore, it is sometimes called a potassium-competitive acid blocker 93 WO 2010/024451 PCT/JP2009/065279 (P-CAB), or an acid pump antagonist (APA). Compound (I) rapidly exhibits the action and shows the maximum efficacy from the initial administration. Furthermore, its metabolism is less influenced by metabolic polymorphism, and variation of 5 efficacy among patients is small. In addition, it has been found that compound (I) is designed to have a characteristic chemical structure wherein (i) the substituent at the 5-position of pyrrole ring is a 2-F-3-pyridyl group, (ii) the substituent at the 4-position of pyrrole ring is a fluorine io atom, and (iii) the 1-position of pyrrole ring is a 2- pyridylsulfonyl group or 3-pyridylsulfonyl group having at least one substituent, and such chemical structure is conducive to a strong proton pump inhibiting activity, and significantly decreases cytotoxicity. Furthermore, it is is characterized in that substitution of the 4-position of pyrrole ring by a fluorine atom in compound (I) lowers basicity (pKa value) of methylaminomethyl moiety due to an electron withdrawing effect of the fluorine atom, and decreases the risk of toxicity expression derived from strong 20 basicity, and that introduction of at least one substituent into A of compound (I) controls the duration of action optimally. Hence, the present invention can provide a clinically useful agent for the prophylaxis or treatment of peptic ulcer (e.g., gastric ulcer, duodenal ulcer, anastomotic 25 ulcer, ulcer caused by non-steroidal anti-inflammatory drug, ulcer due to postoperative stress etc.), Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (Symptomatic GERD), Barrett's esophagus, functional dyspepsia, gastric cancer, 30 stomach MALT lymphoma or hyperacidity? or a suppressant of upper gastrointestinal bleeding due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress; and the like. Since compound (I) shows low toxicity and is superior in water-solubility, in vivo kinetics and efficacy 35 exhibition, it is useful as a pharmaceutical composition. 94 WO 2010/024451 PCT/JP2009/065279

Since compound (I) is stable even under acidic conditions, it can be administered orally as a conventional tablet and the like without formulating into an enteric-coated preparation. . This has an advantageous consequence that the preparation 5 (tablet and the like) can be made smaller, and can be easily swallowed by patients having difficulty in swallowing, particularly the elderly and children. In addition, since it is free of a sustained release effect afforded by enteric-coated preparations, onset of suppression of gastric acid 10 secretion is rapid, and symptoms such as pain and the like can be alleviated rapidly.

[0217]

While some of the embodiments of the present invention have been described in detail in the above, it will, however, is be evident for those of ordinary skill in the art that various modifications and changes may be made to the particular embodiments shown without substantially departing from the novel teaching and advantages of the present invention. Such modifications and changes are encompassed in the spirit and 20 scope of the present invention as set forth in the appended claims .

[0218]

This application is based on patent application Nos. 2008-218851 and 2008-269099 filed in Japan, the contents of 2S which are incorporated in full herein by this reference. 95 □’Ewan pp^a , crnxan ;w:n ατα inia^a pnow pnszn irn nr -jaoa ,ρνιη pxan paoana ma™ na^maa np’ioa .zrtwan rwaa mp’pan ρ-ίΛ axnria ......Gtoca uer □innn Pi? »*···»· · sw ***** ^_ ♦ 23 U3/Z312 122)23-KB fl) .(mcna nannn) cras&amp;’an nwa

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Priority claims
Document	Office	Kind	Date
2008218851	Japan	A	2008-08-27
2008218851	Japan	A	2008-08-27
2008269099	Japan	A	2008-10-17
2008269099	Japan	A	2008-10-17
2009065279	Japan	W	2009-08-26
2009065279	Japan	W	2009-08-26
2008218851	–	–	–
2008269099	–	–	–
JP20080218851	–	–	–
JP20080269099	–	–	–
PCTJP2009065279	–	–	–
WO2009JP65279	–	–	–

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AU2009284867A1	Australia	A1	2010-03-04
CA2735162A1	Canada	A1	2010-03-04
US2010056577A1	United States of America	A1	2010-03-04
WO2010024451A1	World Intellectual Property Organization (WIPO)	A1	2010-03-04
TW201010993A	Taiwan Province of China	A	2010-03-16
UY32074A	Uruguay	A	2010-03-26
AR073136A1	Argentina	A1	2010-10-13
MX2011001955A	Mexico	A	2011-03-29
DOP2011000061A	Dominican Republic	A	2011-04-15
AU2009284867A2	Australia	A2	2011-04-21
IL211335A0	Israel	A0	2011-04-28
ECSP11010912A	Ecuador	A	2011-04-29
EP2318390A1	European Patent Office (EPO)	A1	2011-05-11
CR20110169A	Costa Rica	A	2011-05-16
PE20110300A1	Peru	A1	2011-06-16
KR20110071067A	Republic of Korea	A	2011-06-28
US2011172275A1	United States of America	A1	2011-07-14
CL2011000402A1	Chile	A1	2011-07-29
MA32647B1	Morocco	B1	2011-09-01
CO6321166A2	Colombia	A2	2011-09-20
CN102197033A	China	A	2011-09-21
EA201170384A1	Eurasian Patent Organization (EAPO)	A1	2011-10-31
JP2012501296A	Japan	A	2012-01-19
ZA201101774B	South Africa	B	2012-06-27
HK1157756A	Hong Kong, China	A	2012-07-06
HK1157756A1	Hong Kong, China	A1	2012-07-06
TN2011000094A1	Tunisia	A1	2012-09-05
NZ591793A	New Zealand	A	2012-11-30
GEP20135786B	Georgia	B	2013-03-11
EP2318390B1	European Patent Office (EPO)	B1	2013-05-01
DK2318390T3	Denmark	T3	2013-07-08
PT2318390E	Portugal	E	2013-07-10
SI2318390T1	Slovenia	T1	2013-08-30
HRP20130653T1	Croatia	T1	2013-08-31
SMT201300085B	San Marino	B	2013-09-06
ES2423289T3	Spain	T3	2013-09-19
PL2318390T3	Poland	T3	2013-09-30
US8592597B2	United States of America	B2	2013-11-26
IL211335AThis record	Israel	A	2013-12-31
RS52872B	Serbia	B	2013-12-31
US2014031393A1	United States of America	A1	2014-01-30
UA105185C2	Ukraine	C2	2014-04-25
EA019741B1	Eurasian Patent Organization (EAPO)	B1	2014-05-30
CN102197033B	China	B	2014-07-16
MY152008A	Malaysia	A	2014-08-15
AU2009284867B2	Australia	B2	2014-08-28
PE20141174A1	Peru	A1	2014-09-19
ME01598B	Montenegro	B	2014-09-20
JP5638515B2	Japan	B2	2014-12-10
TWI473798B	Taiwan Province of China	B	2015-02-21
US8969387B2	United States of America	B2	2015-03-03
JO2871B1	Jordan	B1	2015-03-15
US8993598B2	United States of America	B2	2015-03-31
CA2735162C	Canada	C	2015-06-23
BRPI0917705A2	Brazil	A2	2016-02-16
KR101629181B1	Republic of Korea	B1	2016-06-13
CY1114452T1	Cyprus	T1	2016-10-05

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2020-03-31	Patent not in force due to non-payment of renewal feesMM9K	MM9K
2015-07-30	Patent renewedKB	KB
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2014-04-30	Patent grantedGrantedFF	FF

Pyrrole compounds

Abstract

Term

DESCRIPTION PYRROLE COMPOUNDS

TECHNICAL FIELD

X

MEANS OF SOLVING THE PROBLEMS

(I)

EFFECT OF THE INVENTION

(A-2)

(A-2W

14 WO 2010/024451 PCT/JP2009/065279

O

II

A—S—X

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