AU2015268744B2 - 1-Heterocyclylsulfonyl, 3-aminomethyl, 5-(hetero-)aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors - Google Patents

1-Heterocyclylsulfonyl, 3-aminomethyl, 5-(hetero-)aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors Download PDF

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AU2015268744B2
AU2015268744B2 AU2015268744A AU2015268744A AU2015268744B2 AU 2015268744 B2 AU2015268744 B2 AU 2015268744B2 AU 2015268744 A AU2015268744 A AU 2015268744A AU 2015268744 A AU2015268744 A AU 2015268744A AU 2015268744 B2 AU2015268744 B2 AU 2015268744B2
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Atsushi Hasuoka
Masahiro Kajino
Haruyuki Nishida
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Abstract

Abstract The present invention provides a compound having a superior acid secretion inhibitory effect and showing an antiulcer activity and the like. The present invention provides a compound represented by the formula (1) wherein R1 is a nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle, the nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s), R2 is an optionally substituted C614 aryl group, an optionally substituted thienyl group or an optionally substituted pyridyl group, R3 and R4 are each a hydrogen atom, or one of R3 and R4 is a hydrogen atom and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and R5 is an alkyl group or a salt thereof. R C-N R '4

Description

The present invention provides a compound having a superior acid secretion inhibitory effect and showing an antiulcer activity and the like. The present invention provides a compound represented by the formula (I) wherein R1 is a nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle, the nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s), R2 is an optionally substituted C6-14 aryl group, an optionally substituted thienyl group or an optionally substituted pyridyl group, R3 and R4 are each a hydrogen atom, or one of R3 and R4 is a hydrogen atom and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and R5 is an alkyl group or a salt thereof.
Figure AU2015268744B2_D0001
2015268744 15 Dec 2015 l-Heterocyclylsulfonyl, 3-aminomethyl, 5-(hetero-)aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors
Technical Field
The present invention relates to pyrrole compounds having an acid secretion suppressive activity.
Background Art
Proton pump inhibitors represented by omeprazole, which suppress secretion of gastric acid for the treatment of peptic ulcer, reflux esophagitis and the like, have been widely used 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 inhibitors are unstable under acidic conditions, they are often formulated as enteric preparations, in which case several hours are required before expression of the effect. In addition, since the existing proton pump inhibitors show inconsistent treatment effects due to metabolic enzyme polymorphism and drug interaction with pharmaceutical agents such as diazepam and the like, an improvement has been desired. '
As pyrrole compounds having a proton pump inhibitory action, EP-A-0259085 describes a compound represented by the formula:
Figure AU2015268744B2_D0002
and the like.
As compounds having a thromboxane Ά2 (ΤΧΆ2) antagonistic action and a TXA2 synthase inhibitory action, JP-A-8-119936 describes a compound represented by the formula:
2015268744 15 Dec 2015
Figure AU2015268744B2_D0003
wherein rl is carboxy, protected carboxy, carboxy(lower)alkyl, protected carboxy(lower)alkyl, carboxy(lower)alkenyl or protected carboxy(lower)alkenyl, r2 is hydrogen; lower alkyl;
heterocyclic (lower)alkyl optionally having aminoimino or protected aminoimino; heterocyclic (lower)alkenyl; or heterocyclic carbonyl, r3 is hydrogen or lower alkyl, r4 is acyl, r5 is hydrogen, Ao is lower alkylene, and Zo is S or NH, provided when rl is carboxy or protected carboxy, then Zo is io NH.
Moreover, as a therapeutic drug for neoplastic diseases or autoimmune diseases, W02004/103968 describes a compound represented by the formula:
Figure AU2015268744B2_D0004
wherein r6 is aryl, aralkyl or heteroaryl, r7 is aryl or heteroaryl, and r8 is aryl, heteroaryl or optionally substituted·aminomethyl.
Disclosure of the Invention 20 Problems to be Solved by the Invention
A pharmaceutical agent that effectively suppresses gastric acid secretion as known proton pump inhibitors, which is improved in instability under acidic conditions, dispersion of effects due to metabolic enzyme polymorphism and drug interaction, which.are problems of known proton pump inhibitors, is expected to show more superior treatment effect
2015268744 15 Jan 2018 on peptic ulcer, reflux esophagitis and the like. As the situation stands, however, a proton pump inhibitor capable of sufficiently satisfying these requirements has not been found. It would therefore be advantageous if at least preferred embodiments of the present invention were to provide a compound having a superior acid secretion suppressive effect (particularly, proton pump inhibitory effect), which has been improved in these problems.
Means of Solving the Problems The present inventors have conducted various studies and io found that a compound represented by the formula (I):
Figure AU2015268744B2_D0005
SO2
R1 wherein R1 is a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, the monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent (s),
R2 is an optionally substituted C6-14 aryl group, an optionally substituted thienyl group or an optionally substituted pyridyl group,
R3 and R4 are each a hydrogen atom, or one of R3 and R4 is a hydrogen atom and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and
R5 is an alkyl group, or a salt thereof [hereinafter to be abbreviated as compound (I)] unexpectedly has a very strong acid secretion suppressive effect (proton pump inhibitory effect), and is fully satisfactory as a pharmaceutical agent, which resulted in the completion of the present invention.
Accordingly, the present invention relates to the
9793697_1 (GHMatters) P76750.AU.2
2015268744 15 Dec 2015 following.
[1] A compound represented by the formula (I):
Figure AU2015268744B2_D0006
wherein R1 is a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, the monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s), R2 is an optionally substituted C6-n aryl group, an optionally substituted thienyl io group or an optionally substituted pyridyl group, R3 and R4 are each a hydrogen atom, or one of R3 and R4 is a hydrogen atom and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and R5 is an alkyl group, or a salt thereof.
is [2] A compound represented by the formula (I):
Figure AU2015268744B2_D0007
wherein R1.is a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, the monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s), R2 is an optionally substituted Ce-u aryl group or an optionally substituted thienyl group, R3 and R4 are each a hydrogen atom, or one of R3 and R4 is a hydrogen atom and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom,
2015268744 19 Feb 2016 a cyano group or a nitro group, and R5 is an alkyl group, or a salt thereof.
[3] The compound of the above-mentioned [1] or [2], wherein R1 is a monocyclic nitrogen-containing heterocyclic group.
s [4] The compound of the above-mentioned [1] or [2], wherein the monocyclic nitrogen-containing heterocyclic group is a pyridyl group.
[5] The compound of the above-mentioned [1] or [2], wherein Rz is a phenyl group optionally substituted by 1 to 5 io substituents selected from (i) a halogen atom and (ii) a Ci-6 alkyl optionally substituted by 1 to 5 halogen atoms.
[6] The compound of the above-mentioned [1], wherein R2 Is a pyridyl group optionally substituted by 1 to 4 substituent (s) selected from Ci-6 alkyl, a halogen atom, alkoxy, is cyano, acyl, nitro and amino.
[7] The compound of the above-mentioned [1] or [2], wherein R3 and R4 are each a hydrogen atom.
[8] The compound of the above-mentioned [1] or [2], wherein R5 is a methyl group.
[9] 1—{5—(2-Fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl)~ lH-pyrrol-3-yl]-N-methylmethanamine or a salt thereof.
[10] 1-[4-Fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]-N-methylmethanamine or a salt thereof.
[11] N-Methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-325 ylsulfonyl)-lH-pyrrol-3-yl]methanamine or a salt thereof.
[12] 1-[5-(2-Fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine or a salt thereof.
[13] 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-IH-pyrrol3-yl]-N-methylmethanamine or a salt thereof.
[14] N-Methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl) lH-pyrrol-3-yl]methanamine or a salt thereof.
[15] A prodrug of the compound of the above-mentioned [1] or [2'] .
[16] A pharmaceutical composition comprising the compound of the above-mentioned [1] or [2] or a prodrug thereof.
2015268744 15 Jan 2018 [17] The pharmaceutical composition of the above-mentioned [16], which is an acid secretion inhibitor.
[18] The pharmaceutical composition of the above-mentioned [16], which is a potassium-competitive acid blocker.
[19] The pharmaceutical composition of the above-mentioned [16], which is an agent for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress.
[20] A method of treating or preventing peptic ulcer,
Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or a method of inhibiting upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress, which comprises administering an effective amount of the compound of the above-mentioned [1] or [2] or a prodrug thereof to a mammal.
[21] Use of the compound of the above-mentioned [1] or [2] or a prodrug thereof for the production of a pharmaceutical composition for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress .
9793697_1 (GHMatters) P76750.AU.2
2015268744 25 Jan 2018
The present invention as claimed herein is described in the following items 1 to 24:
1. A compound represented by the formula (I):
Figure AU2015268744B2_D0008
SO2
R1 wherein R1 is an aromatic or saturated or unsaturated nonaromatic monocyclic nitrogen-containing heterocyclic group containing, as a ring-constituting atom, at least one nitrogen atom and being optionally condensed with a benzene ring or an 10 aromatic or non-aromatic heterocycle, the monocyclic nitrogencontaining heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has 1 to 5 substituent(s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) Ci-6 alkoxy 15 optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) monoCg-i4 arylamino, (15) mono-C7_i6 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) C1-6 alkoxy-carbonyl, (24) C6-14 aryloxycarbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 aryl25 carbamoyl, (30) C1-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32)
C1-6 alkylsulfinyl, (33) C6-14 arylsulfinyl, (34) formylamino, (35) C1-6 alkyl-carbonylamino, (36) C6-14 aryl-carbonylamino, (37) C1-6 alkoxy-carbonylamino, (38) C1-6 alkylsulfonylamino, (39) Cg-i4 arylsulf onylamino, (40) C1-6 alkyl-carbonyloxy, (41) 30 C6-14 aryl-carbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) mono9915521_1 (GHMatters) P76750.AU.2
6a
2015268744 25 Jan 2018
Ci-6 alkyl-carbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45)
C6-14 aryl-carbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected 5 from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 alkylenedioxy, (49) C3-7 cycloalkyl, (50) C1-6 10 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6 alkenyl group optionally having 1 to 3 halogen atoms, (52) a C2-6 alkynyl group, and (53) a C1-6 alkyl group substituted by 1 to 3 hydroxy, R2 is (i) a C6-14 aryl group optionally having 1 to 5 substituent(s) selected from the group consisting of (1) 15 a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) mono20 C6-14 arylamino, (15) mono-C7_i6 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) C1-6 alkoxy-carbonyl, (24) C6-14 aryloxycarbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 arylcarbamoyl, (30) C1-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32)
C1-6 alkylsulfinyl, (33) C6-14 arylsulfinyl, (34) formylamino, (35) C1-6 alkyl-carbonylamino, (36) C6-14 aryl-carbonylamino, (37) C1-6 alkoxy-carbonylamino, (38) C1-6 alkylsulfonylamino, (39) C6-14 arylsulf onylamino, (40) C1-6 alkyl-carbonyloxy, (41)
C6-14 aryl-carbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) monoC1-6 alkyl-carbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45)
C6-14 aryl-carbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected
9915521_1 (GHMatters) P76750.AU.2
6b
2015268744 25 Jan 2018 from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen 5 atom, (48) C1-3 alkylenedioxy, (49) C3-7 cycloalkyl, (50) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6 alkenyl group optionally having 1 to 3 halogen atoms, (52) a C2-6 alkynyl group, and (53) a C1-6 alkyl group substituted by 1 to 3 hydroxy, (ii) a thienyl group optionally having 1 to 4 10 substituent(s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 15 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) monoCg-i4 arylamino, (15) mono-C7_i6 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) C1-6 alkoxy-carbonyl, (24) C6-14 aryloxy20 carbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 arylcarbamoyl, (30) C1-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32)
C1-6 alkylsulfinyl, (33) C6-14 arylsulfinyl, (34) formylamino, (35) C1-6 alkyl-carbonylamino, (36) C6-14 aryl-carbonylamino, (37) C1-6 alkoxy-carbonylamino, (38) C1-6 alkylsulfonylamino, (39) C6-14 arylsulf onylamino, (40) C1-6 alkyl-carbonyloxy, (41) C6-14 aryl-carbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) monoC1-6 alkyl-carbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) C6-14 aryl-carbamoyloxy, (46) a 5- to 7-membered saturated 30 cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen
9915521_1 (GHMatters) P76750.AU.2
6c
2015268744 25 Jan 2018 atom, (48) C1-3 alkylenedioxy, (49) C3-7 cycloalkyl, (50) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6 alkenyl group optionally having 1 to 3 halogen atoms, (52) a C2-6 alkynyl group, and (53) a C1-6 alkyl group substituted by 1 5 to 3 hydroxy, or (iii) a pyridyl group optionally having 1 to 4 substituent (s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally 10 having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) monoCg-i4 arylamino, (15) mono-C7_i6 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, 15 (22) carboxyl, (23) C1-6 alkoxy-carbonyl, (24) C6-14 aryloxycarbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 arylcarbamoyl, (30) C1-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32)
C1-6 alkylsulfinyl, (33) C6-14 arylsulfinyl, (34) formylamino, (35) C1-6 alkyl-carbonylamino, (36) C6-14 aryl-carbonylamino, (37) C1-6 alkoxy-carbonylamino, (38) C1-6 alkylsulfonylamino, (39) C6-14 arylsulf onylamino, (40) C1-6 alkyl-carbonyloxy, (41) C6-14 aryl-carbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) monoC1-6 alkyl-carbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) 25 Cg-i4 aryl-carbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, 30 besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 alkylenedioxy, (49) C3-7 cycloalkyl, (50) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6 alkenyl group optionally having 1 to 3 halogen atoms, (52) a
C2-6 alkynyl group, and (53) a C1-6 alkyl group substituted by 1
9915521_1 (GHMatters) P76750.AU.2
6d
2015268744 25 Jan 2018 to 3 hydroxy, R3 and R4 are each a hydrogen atom, or one of R3 and R4 is a hydrogen atom and the other is (i) a C1-4 alkyl group optionally having 1 to 3 substituent(s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) 5 cyano, (4) hydroxy, (5) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) mono-C6-i4 arylamino, (15) mono70 C7-16 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) Ci6 alkoxy-carbonyl, (24) C6-14 aryloxy-carbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 15 alkyl-carbamoyl, (29) C6-14 aryl-carbamoyl, (30) C1-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32) C1-6 alkylsulfinyl, (33) C6-14 arylsulf inyl, (34) formylamino, (35) C1-6 alkylcarbonylamino, (36) C6-14 aryl-carbonylamino, (37) C1-6 alkoxycarbonylamino, (38) C1-6 alkylsulfonylamino, (39) C6-14 arylsulf onylamino, (40) C1-6 alkyl-carbonyloxy, (41) C6-14 arylcarbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) mono-Ci-6 alkylcarbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) C6-14 arylcarbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 30 alkylenedioxy, and (49) C3-7 cycloalkyl, (ii) an acyl group selected from the group consisting of a C1-7 alkanoyl group, a C6-14 aryl-carbonyl group, a C1-6 alkoxy-carbonyl group, a C6-14 aryloxy-carbonyl group, a C7-19 aralkyl-carbonyl group, a C7-19 aralkyloxy-carbonyl group, a 5- or 6-membered heterocycle25 carbonyl group or condensed heterocycle-carbonyl group thereof,
9915521_1 (GHMatters) P76750.AU.2
6e
2015268744 25 Jan 2018 and a 5- or 6-membered heterocycle-acetyl group, wherein when the acyl group is a C1-7 alkanoyl group or a C1-6 alkoxy-carbonyl group, the acyl group is optionally substituted by 1 to 3 C1-4 alkylthio groups, halogen, C1-6 alkoxy groups, a nitro group, 5 C1-6 alkoxy-carbonyl groups, mono- or di-Ci-6 alkylamino groups, C1-6 alkoxyimino groups or hydroxyimino, wherein when the acyl group is a C6-14 aryl-carbonyl group, a C6-14 aryloxy-carbonyl group, a C7-19 aralkyl-carbonyl group, a C7-19 aralkyloxycarbonyl group, a 5- or 6-membered heterocycle-carbonyl group or a 510 or 6-membered heterocycle-acetyl group, the acyl group is optionally substituted by 1 to 5 C1-6 alkyl groups, C3-6 cycloalkyl groups, C2-6 alkenyl groups, C2-6 alkynyl groups, C1-6 alkoxy groups, C1-7 alkanoyl groups, C6-14 aryl-carbonyl groups, C1-6 alkoxy-carbonyl groups, C6-14 aryloxy-carbonyl groups, C7-19 15 aralkyl-carbonyl groups, C7-19 aralkyloxy-carbonyl groups, nitro, amino, hydroxy, cyano, sulfamoyl, mercapto, halogen, or C1-4 alkylthio groups, (iii) a halogen atom, (iv) a cyano group or (v) a nitro group, and R5 is a C1-6 alkyl group, or a salt thereof;
excluding 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine or a salt thereof.
2. The compound according to item 1 and represented by the
Figure AU2015268744B2_D0009
wherein R1 is a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, the monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a 30 heterocycle optionally has 1 to 5 substituent(s) selected from
9915521_1 (GHMatters) P76750.AU.2
6f
2015268744 25 Jan 2018 the group consisting of (1) a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) Ci_6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen 5 atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) mono-C6-i4 arylamino, (15) monoC7-16 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) Ci10 6 alkoxy-carbonyl, (24) C6-14 aryloxy-carbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 aryl-carbamoyl, (30) C1-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32) C1-6 alkylsulfinyl, (33) Cg-i4 arylsulf inyl, (34) formylamino, (35) C1-6 alkyl75 carbonylamino, (36) C6-14 aryl-carbonylamino, (37) C1-6 alkoxycarbonylamino, (38) C1-6 alkylsulfonylamino, (39) C6-14 arylsulfonylamino, (40) C1-6 alkyl-carbonyloxy, (41) C6-14 arylcarbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) mono-Ci-6 alkylcarbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) C6-14 aryl25 carbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 alkylenedioxy, (49) C3-7 cycloalkyl, (50) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6 alkenyl group optionally having 1 to 3 halogen atoms, (52) a C2-6 alkynyl group, and (53) a C1-6 alkyl group substituted by 1 to 3 hydroxy, R2 is (i) a C6-14 aryl group optionally having 1 to 5 substituent(s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7)
C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally
9915521_1 (GHMatters) P76750.AU.2
6g
2015268744 25 Jan 2018 having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) monoCg-i4 arylamino, (15) mono-C7_i6 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, 5 (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) C1-6 alkoxy-carbonyl, (24) C6-14 aryloxycarbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 arylcarbamoyl, (30) C1-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32) 10 C1-6 alkylsulfinyl, (33) C6-14 arylsulfinyl, (34) formylamino, (35) C1-6 alkyl-carbonylamino, (36) C6-14 aryl-carbonylamino, (37) C1-6 alkoxy-carbonylamino, (38) C1-6 alkylsulfonylamino, (39) Cg-i4 arylsulf onylamino, (40) C1-6 alkyl-carbonyloxy, (41) C6-14 aryl-carbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) mono75 C1-6 alkyl-carbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45)
C6-14 aryl-carbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a
5- to 10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 alkylenedioxy, (49) C3-7 cycloalkyl, (50) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6 alkenyl group optionally having 1 to 3 halogen atoms, (52) a C2-6 alkynyl group, and (53) a C1-6 alkyl group substituted by 1 to 3 hydroxy, or (ii) a thienyl group optionally having 1 to 4 substituent (s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) C1-6 alkoxy 30 optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) monoCg-i4 arylamino, (15) mono-C7_i6 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino,
9915521_1 (GHMatters) P76750.AU.2
6h
2015268744 25 Jan 2018 (19) formyl, (20) Ci_6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) C1-6 alkoxy-carbonyl, (24) C6-14 aryloxycarbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 aryl5 carbamoyl, (30) C1-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32)
C1-6 alkylsulfinyl, (33) C6-14 arylsulfinyl, (34) formylamino, (35) C1-6 alkyl-carbonylamino, (36) C6-14 aryl-carbonylamino, (37) C1-6 alkoxy-carbonylamino, (38) C1-6 alkylsulfonylamino, (39) Cg-i4 arylsulf onylamino, (40) C1-6 alkyl-carbonyloxy, (41) 10 C6-14 aryl-carbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) monoC1-6 alkyl-carbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) C6-14 aryl-carbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected 15 from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 alkylenedioxy, (49) C3-7 cycloalkyl, (50) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6 alkenyl group optionally having 1 to 3 halogen atoms, (52) a C2-6 alkynyl group, and (53) a C1-6 alkyl group substituted by 1 to 3 hydroxy, R3 and R4 are each a hydrogen atom, or one of R3 and R4 is a hydrogen atom and the other is (i) a C1-4 alkyl group optionally having 1 to 3 substituent (s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen 30 atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) mono-C6-i4 arylamino, (15) monoC7-16 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) Ci25 6 alkoxy-carbonyl, (24) C6-14 aryloxy-carbonyl, (25) carbamoyl,
9915521_1 (GHMatters) P76750.AU.2
2015268744 25 Jan 2018 (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 aryl-carbamoyl, (30) Ci_6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32) Ci_6 alkylsulfinyl, (33) Cg-i4 arylsulf inyl, (34) formylamino, (35) Ci_6 alkyl5 carbonylamino, (36) C6-14 aryl-carbonylamino, (37) Ci_6 alkoxycarbonylamino, (38) Ci_6 alkylsulfonylamino, (39) C6-14 arylsulfonylamino, (40) Ci_6 alkyl-carbonyloxy, (41) C6-14 arylcarbonyloxy, (42) Ci-6 alkoxy-carbonyloxy, (43) mono-Ci-6 alkylcarbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) C6-14 aryl20 carbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, besides 15 carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 alkylenedioxy, and (49) C3-7 cycloalkyl, (ii) an acyl group selected from the group consisting of a C1-7 alkanoyl group, a C6-14 aryl-carbonyl group, a C1-6 alkoxy-carbonyl group, a C6-14 aryloxy-carbonyl group, a C7-19 aralkyl-carbonyl group, a C7-19 aralkyloxy-carbonyl group, a 5- or 6-membered heterocyclecarbonyl group or condensed heterocycle-carbonyl group thereof, and a 5- or 6-membered heterocycle-acetyl group, wherein when the acyl group is a C1-7 alkanoyl group or a C1-6 alkoxy-carbonyl group, the acyl group is optionally substituted by 1 to 3 C1-4 alkylthio groups, halogen, C1-6 alkoxy groups, a nitro group,
C1-6 alkoxy-carbonyl groups, mono- or di-Ci-6 alkylamino groups, C1-6 alkoxyimino groups or hydroxyimino, wherein when the acyl group is a C6-14 aryl-carbonyl group, a C6-14 aryloxy-carbonyl 30 group, a C7-19 aralkyl-carbonyl group, a C7-19 aralkyloxycarbonyl group, a 5- or 6-membered heterocycle-carbonyl group or a 5or 6-membered heterocycle-acetyl group, the acyl group is optionally substituted by 1 to 5 C1-6 alkyl groups, C3-6 cycloalkyl groups, C2-6 alkenyl groups, C2-6 alkynyl groups, C1-6 alkoxy groups, C1-7 alkanoyl groups, C6-14 aryl-carbonyl groups,
6j
9915521_1 (GHMatters) P76750.AU.2
2015268744 25 Jan 2018
Ci-6 alkoxy-carbonyl groups, C6-14 aryloxy-carbonyl groups, C7-19 aralkyl-carbonyl groups, C7-19 aralkyloxy-carbonyl groups, nitro, amino, hydroxy, cyano, sulfamoyl, mercapto, halogen, or C1-4 alkylthio groups, (iii) a halogen atom, (iv) a cyano group or 5 (v) a nitro group, and R5 is a C1-6 alkyl group, or a salt thereof.
3. The compound of item 1 or 2, wherein R1 is a monocyclic nitrogen-containing heterocyclic group.
4. The compound of item 1 or 2, wherein the monocyclic nitrogen-containing heterocyclic group is a pyridyl group.
5. The compound of item 1 or 2, wherein R2 is a phenyl group optionally substituted by 1 to 5 substituents selected from (i) a halogen atom and (ii) a C1-6 alkyl optionally substituted by 1 to 5 halogen atoms.
6. The compound of item 1, wherein R2 is a pyridyl group optionally substituted by 1 to 4 substituent (s) selected from C1-6 alkyl, a halogen atom, C1-6 alkoxy, cyano, acyl, nitro and amino .
7. The compound of item 1 or 2, wherein R3 and R4 are each a hydrogen atom.
8. The compound of item 1 or 2, wherein R5 is a methyl group.
9. 1-{5-(2-Fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]30 lH-pyrrol-3-yl}-N-methylmethanamine or a salt thereof.
10. 1-[4-Fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-3yl]-N-methylmethanamine or a salt thereof.
9915521_1 (GHMatters) P76750.AU.2
6k
2015268744 25 Jan 2018
11. N-Methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methanamine or a salt thereof.
12. 1-[5- (2-Fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H5 pyrrol-3-yl]-N-methylmethanamine or a salt thereof.
13. N-Methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl]methanamine or a salt thereof.
io 14. A prodrug of the compound of item 1 or 2.
15. A pharmaceutical composition comprising the compound of item 1 or 2 or a prodrug thereof.
16. A pharmaceutical composition comprising 1-[5-(2fluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]-Nmethylmethanamine or a salt thereof or a prodrug thereof.
17. The pharmaceutical composition of item 15 or 16, an acid secretion inhibitor.
which is
18. The pharmaceutical composition of item 15 or 16, which is a potassium-competitive acid blocker.
19. The pharmaceutical composition of item 15 or 16, which is an agent for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress .
9915521_1 (GHMatters) P76750.AU.2
2015268744 25 Jan 2018
20. A method of treating or preventing peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (Symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or a method of inhibiting upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress, which comprises administering an effective amount of the compound of item 1 or 2 or a prodrug thereof to a mammal.
21. Use of the compound of item 1 or 2 or a prodrug thereof for the production of a pharmaceutical composition for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison is syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (Symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress.
22. A method of treating or preventing peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (Symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or a method of inhibiting upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress, which comprises administering an effective amount of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine or a salt thereof or a prodrug thereof to a mammal.
23. Use of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H35 pyrrol-3-yl]-N-methylmethanamine or a salt thereof or a
9915521_1 (GHMatters) P76750.AU.2
6m
2015268744 25 Jan 2018 prodrug thereof for the production of a pharmaceutical composition for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (Symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress .
o
24. A compound according to item 1 and represented by the
Figure AU2015268744B2_D0010
wherein R1 is a pyridyl group optionally substituted by 1 to 3 15 substituents selected from (i) Ci_6 alkyl optionally substituted by 1 to 3 halogen atoms and (ii) Ci_6 alkoxy optionally substituted by 1 to 3 halogen atoms, R2 is a phenyl group optionally substituted by 1 to 5 substituents selected from (i) a halogen atom and (ii) Ci_6 alkyl optionally substituted by
2o 1 to 3 halogen atoms, R3 and R4 are each a hydrogen atom, and R5 is methyl.
Effect of the Invention
Since compound (I) shows a superior proton pump
9915521_1 (GHMatters) P76750.AU.2
6n
2015268744 15 Dec 2015 inhibitory effect (while conventional proton pump inhibitors such as omeprazole, lansoprazole etc. form a covalent bond with a cysteine residue of H+/K+-ATPase and irreversibly inhibit the enzyme activity, since compound (I) inhibits the proton pump (H+/K+-ATPase) activity reversibly and in a K+ antagonist inhibitory manner to consequently suppress acid secretion, it is sometimes referred to as a potassiumcompetitive acid blocker: P-CAB or an acid pump antagonist (ACPA or APA)), it can provide a clinically useful pharmaceutical composition for the prophylaxis and/or treatment of peptic ulcer (e.g., gastric ulcer, gastric ulcer due to postoperative stress, duodenal ulcer, anastomotic ulcer, ulcer caused by non-steroidal anti-inflammatory agents, ulcer due to postoperative stress etc.); Zollinger-Ellison syndrome; gastritis; erosive esophagitis; reflux esophagitis such as erosive reflux esophagitis and the like; symptomatic gastroesophageal reflux disease (symptomatic GERD) such as non-erosive reflux disease or gastroesophageal reflux disease free of esophagitis and the like; functional dyspepsia;
gastric cancer (including gastric cancer associated with promoted production of interleukin-ΐβ due to gene polymorphism of interleukin-1); stomach MALT lymphoma; gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress (e.g. stress caused by major surgery requiring postoperative intensive management, and cerebrovascular disorder, head trauma, multiple organ failure and extensive burn, each requiring intensive treatment) and the like. Furthermore, compound (I) is used for the prophylaxis and/or treatment of airway disorders; asthma and the like, pre-anesthetic administration, eradication of Helicobacter pylori or eradication assistance and the like. Since compound (I) shows low toxicity and is superior in water-solubility, in vivo kinetics and efficacy expression, it is useful as a pharmaceutical composition. Moreover, since 7
2015268744 15 Dec 2015 compound (I) is stable even under acidic conditions, which enables oral administration of the compound as a conventional tablet and the like without formulating an enteric-coated preparation. This has a consequence that the preparation of 5 tablet and the like can be made smaller, which is advantageous in that it is easily swallowed by patients having difficulty in swallowing, particularly the elderly and children. In addition, since a sustained release effect afforded by enteric-coated preparations is absent, expression of a gastric 10 acid secretion-suppressive action is rapid, and alleviation of symptoms such as pain and the like is rapid.
Best Mode for Embodying the Invention In the formula (I), as the nitrogen-containing monocyclic heterocyclic group optionally condensed with a 15 benzene ring or a heterocycle for R1, (1) a nitrogen-containing monocyclic heterocyclic group, and (2) a fused ring group represented by the formula:
Figure AU2015268744B2_D0011
20 wherein ring A is a nitrogen-containing monocyclic heterocyclic group, ring B is a benzene ring or a heterocycle, a and b are each a bridgehead ring-constituting atom (e.g., a carbon atom, a nitrogen atom and the. like) , and = shows a single bond or a double bond, provided that a bond to an -SO225 group in the formula (I) is present in a ring A-constituting atom (ring atom) other than the bridgehead ring-constituting atoms a and b, can be mentioned.
As used herein, ring A needs only to contain, as a ring A-constituting atom (ring atom), at least one (preferably 1 to 30 4, more preferably 1 or 2) nitrogen atom, and one or both of the bridgehead ring-constituting atoms a and b may be nitrogen atoms.
2015268744 15 Dec 2015
The nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s), and-the substituent(s) may be present in any of ring A and ring B.
As the nitrogen-containing monocyclic heterocyclic group of the nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle and the above-mentioned ring A, for example, an aromatic nitrogen-containing monocyclic heterocyclic group, a io saturated or unsaturated non-aromatic nitrogen-containing monocyclic heterocyclic group (aliphatic nitrogen-containing monocyclic heterocyclic group) and the like containing, as a . ring-constituting atom (ring atom), at least one (preferably 1 to 4, more preferably 1 or 2) nitrogen atom can be mentioned.
As the aromatic nitrogen-containing monocyclic heterocyclic group, for example, aromatic nitrogen-containing monocyclic heterocyclic groups such as pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl (lH-imidazol1-yl, lH-imidazol-4-yl etc.), pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3triazolyl, 1,2,4-triazolyl (1,2,4-triazol-l-yl, 1,2,4-triazol4-yl etc.), tetrazolyl, pyridyl (2—, 3- or 4-pyridyl etc.), pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and N-oxide forms thereof and the like can be mentioned. Of these, a 5- or 6-membered aromatic nitrogen-containing monocyclic heterocyclic group is preferable, and thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl and pyridazinyl are preferable, and pyridyl is particularly preferable.
As the saturated or unsaturated non-aromatic nitrogencontaining monocyclic heterocyclic group, partially reduced forms (e.g., imidazolinyl, tetrahydropyrimidinyl and the like) of the above-mentioned aromatic nitrogen-containing monocyclic heterocyclic group and, for example, azetidinyl, pyrrolidinyl, piperidyl (2-, 3- or 4-piperidyl), morpholinyl,
2015268744 15 Dec 2015 thiomorpholinyl, piperazinyl (1-piperazinyl etc.), homopiperazinyl and the like can be mentioned. Of these, a 5or β-merabered non-aromatic nitrogen-containing monocyclic heterocyclic group is preferable.
As the heterocycle optionally condensed with a nitrogen-containing monocyclic heterocyclic group, for example, an aromatic heterocycle or non-aromatic heterocycle can be mentioned.
As the aromatic heterocycle, for example, 5- or βίο membered aromatic heteromonocyclic rings such as a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, an imidazole ring, a pyrazole ring, a 1,2,3-oxadiazole ring, a
1.2.4- oxadiazole ring, a 1,3,4-oxadiazole ring, a furazan is ring, a 1,2, 3-thiadiazole ring, a 1,2,4-thiadiazole ring, a
1.3.4- thiadiazole ring, a 1,2,3-triazole ring, a 1,2,4triazole ring, tetrazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring and the like and, for example, 8- to 12-membered aromatic fused heterocycles such as a benzofuran ring, an isobenzofuran ring, a benzo[b]thiophene ring, an indole ring, an isoindole ring, a IH-indazole ring, a benzindazole ring, a benzoxazole ring, a 1,2-benzoisoxazole ring, a benzothiazole ring, a benzopyran ring, a 1,2-benzoisothiazole ring, a ΙΗ-benzotriazole ring, a quinoline ring, an isoquinoline ring, a cinnoline ring, a quinazoline ring, a quinoxaline ring, a phthalazine ring, a naphthyridine ring, a purine ring, a pteridine ring, a carbazole ring, an cc-carboline ring, a β-carboline ring, a γcarboline ring, an acridine ring, a phenoxazine ring, a phenothiazine ring, a phenazine ring, a phenoxathiine ring, a thianthrene ring, a phenanthridine ring, a phenanthrone ring, an indolizine ring, a pyrrolo[1,2-b]pyridazine ring, a py'razolo [1,5-a]pyridine ring, an imidazo[1,2-a]pyridine ring, an imidazo[1,5-a]pyridine ring, an imidazo[1,2-b]pyridazine ring, an imidazo[1,2-a]pyrimidine ring, a 1,2,4-triazolo[4,310
2015268744 15 Dec 2015
a]pyridine ring, a 1,2,4-triazolo[4, 3-b]pyridazine ring and the like (preferably, a heterocycle wherein the aforementioned 5- or 6-membered aromatic heteromonocyclic ring is condensed with a benzene ring or a heterocycle wherein the same or different two heterocycles of the aforementioned 5- or 6membered aromatic heteromonocyclic ring are condensed, more preferably a heterocycle wherein the aforementioned 5- or 6membered aromatic monocyclic heterocyclic group is condensed with a benzene ring, preferably imidazopyrimidinyl etc.) and io the like can be mentioned.
As the non-aromatic heterocycle, for example, 3- to 8mexnbered saturated or unsaturated non-aromatic heterocycles such as an oxirane ring, an azetidine ring, an oxetane ring, a thietane ring, a pyrrolidine ring, a tetrahydrofuran ring, a thioran ring, a piperidine ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a piperazine ring, a 3-hexahydrocyclopenta[c]pyrrole ring, a homopiperidine ring, a homopiperazine ring and the like, or non-aromatic heterocycles wherein the double bonds of the aforementioned aromatic heteromonocyclic ring or aromatic fused heterocycle are partly or entirely saturated such as a dihydropyridine ring, a dihydropyrimidine ring, a 1,2,3,4-tetrahydroquinoline ring, a
1,2,3,4-tetrahydroisoquinoline ring and the like, and the like can be mentioned.
As preferable nitrogen-containing monocyclic heterocyclic group condensed with a benzene ring or a heterocycle, for example, nitrogen-containing aromatic fused heterocyclic groups such as 8- to 16-membered (preferably 8- to 12membered) nitrogen-containing aromatic bicyclic fused heterocyclic groups such as 2- or 3-indolyl, 1- or 3isoindolyl, lH-indazol-3-yl, 2-benzimidazolyl, 2-benzoxazolyl, 3-benzoisoxazolyl, 2-benzothiazolyl, 3-benzoisothiazolyl, 2-,
3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl, 3- or 4-cinnolinyl, 2- or 4-quinazolinyl, 2- or 3-quinoxalinyl, 1- or 435 phthalazinyl, naphthyridinyl, purinyl, pteridinyl, 1,711
2015268744 15 Dec 2015 phenanthrolin-2-, 3- or 4-yl, 1-, 2- or 3-indolizinyl, pyrrolo [ 1, 2-b] pyridazinyl,. pyrazolo [ 1, 5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,2-b]pyrazolyl, imidazo[1,5a] pyridyl, imidazo[4,5-c]pyridyl, pyrazolo[1,5-a]pyrimidinyl, pyrazolo[1,5-c]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,5-b]pyridazinyl, pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyrimidinyl, 1,2,4triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, [1.2.4] triazolo[1,2-a]pyridazinyl, [1,2,3]triazolo[1,520 a]pyrimidinyl, [1,2,4]triazolo[1,5-c]pyrimidinyl, [1.2.4] triazolo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, pyrazolo[5,1-b]thiazolyl, pyrrolo[2,1-f][1,2,4]triazinyl, pyrrolo[1, 2-b]pyridazinyl, pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridyl, thieno[3,2-b]pyrimidinyl, thieno[2,325 b]pyridyl, thieno[2,3-c]pyridyl, thieno[3,2-b]pyridyl, thieno[3,2-c]pyridyl, pyrido[2,3-b]pyrazyl, pyrido[3,4b] pyrazyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl and the like, and the like, and the like can be mentioned. As the nitrogen-containing aromatic fused heterocycle, fused pyridine wherein a pyridine ring is condensed with one or two (preferably one) of the aforementioned 5- or 6-membered nitrogen-containing aromatic monocyclic heterocycles or one or two (preferably one) benzene rings (when condensed with a benzene ring, the pyridine ring has a bond), fused pyrimidine wherein a pyrimidine ring is condensed with one or two (preferably one) of the aforementioned 5 or 6-membered nitrogen-containing aromatic monocyclic heterocycles, or one or two (preferably one) benzene rings (when condensed with a benzene ring, the pyrimidine ring has a bond) and the like are preferable.
As the non-aromatic nitrogen-containing heterocycle, for example, 3- to 8-membered (preferably 5- or 6-membered) nitrogen-containing saturated or unsaturated (preferably saturated) non-aromatic heterocycle (aliphatic nitrogen55 containing heterocycle) such as azetidine, pyrrolidine,
2015268744 15 Dec 2015 imidazolidine, thiazolidine, oxazolidine, piperidine, morpholine, thiomorpholine, piperazine and the like, or nitrogen-containing non-aromatic heterocycle wherein the double bonds of the aforementioned nitrogen-containing aromatic monocyclic heterocycle or nitrogen-containing aromatic fused heterocycle are partly or entirely saturated, such as 1,2,3,4-tetrahydroquinoline, 1,2,3,4tetrahydroisoquinoline and the like, and the like can be mentioned.
io As the nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle, a 5- or 6-membered aromatic nitrogen-containing monocyclic heterocyclic group is preferable from among those mentioned above. Of them, a 6-membered aromatic nitrogen-containing is heterocyclic group such as pyridyl (e.g., 2-, 3- or 4-pyridyl etc.), pyrimidinyl (e.g., 2-, 4- or 5-pyrimidinyl etc.), pyridazinyl (e.g., 3- or 4-pyridazinyl etc.) and the like is preferable, and pyridyl is particularly preferable.
As the substituent that the nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle may have, (1) a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom etc.), (2) nitro, (3) cyano, (4) hydroxy, (5) Ci_6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec25 butoxy, pentyloxy, hexyloxy, fluoromethoxy etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (6) C6-i4 aryloxy (e.g., phenyloxy, naphthyloxy etc.), (7) C7-ie aralkyloxy (e.g., benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy, 230 naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy, 4phenylbutyloxy, 5-phenylpentyloxy etc.), (8) mercapto, (9) Ci-6 alkylthio (e.g., methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4, 4,4-trifluorobutylthio, pentylthio, hexylthio etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine,
2015268744 15 Dec 2015 chlorine, bromine, iodine), (10) C6-i4 arylthio (e.g., phenylthio, naphthylthio etc.), (11) C7-16 aralkylthio (e.g., benzylthio, phenethylthio, diphenylmethylthio, 1naphthylmethylthio, 2-naphthylmethylthio, 2,25 diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 5phenylpentylthio etc.), ¢12) amino, (13) mono-Ci-s alkylamino (e.g., methylamino, ethylamino etc.), (14) mono-Cs-u arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino etc.), (15) mono-C7-i6 aralkylamino (e.g., benzylamino etc.), (16) di10 C1-6 alkylamino (e.g., dimethyl amino, diethylamino etc.), (17) di-Cg-i4 arylamino (e.g., diphenylamino etc.), (18) di-C7-ie aralkylamino (e.g., dibenzylamino etc.), (19) formyl, (20) Ci-g alkyl-carbonyl (e.g., acetyl, propionyl etc.), ¢21) C6-i4 arylcarbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.), (22) is carboxyl, (23) Ci-β alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.), (24) C6-i4 aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.), (28) di-Ci_6 alkyl-carbamoyl (e.g., dimethyl carbamoyl, di ethyl carbamoyl, ethylmethylcarbamoyl etc.), (29) Ce-i4 aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), (30) Ci_6 alkylsulfonyl (e.g., methyl sulfonyl, ethylsulfonyl etc.), (31) C6-i4 arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl etc.), (32) Ci-β alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.), ¢33) Ce-14 arylsulfinyl (e.g., phenyl sulfinyl, 1naphthylsulfinyl, 2-naphthylsulfinyl etc.), (34) formylamino, (35) Ci_6 alkyl-carbonylamino (e.g., acetylamino etc.), (36) C6 14 aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37) Ci-β alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino etc.), (38) Ci_6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino etc.), (39) C6-i4 arylsulfonylamino (e.g.,
2015268744 15 Dec 2015 phenylsulfonylamino, 2-naphthylsulfonylamino, 1naphthylsulfonylamino etc.), (40) Ci-β alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.), (41) Ce-14 aryl-carbonyloxy (e.g., benzoyloxy, naphthyl carbonyl oxy etc.), (42) Ci_6 alkoxy5 carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy etc.), (43) mono-Ci_6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.), ¢44) di-Ci_6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy etc.), (45) C6-i4 io aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to 7-membered saturated cyclic amino (e.g., pyrrolidin-l-yl, piperidino, piperazin-1yl, morpholino, thiomorpholino, hexahydroazepin-l-yl etc.) optionally containing, besides one nitrogen atom and carbon is atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,
3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.) containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1.-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), (49) C3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.), (50) C1-6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (51) a C2-s alkenyl group (e.g., allyl, isopropenyl, isobutenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (52) a C2-6 alkynyl group (e.g.,
2015268744 15 Dec 2015 propargyl, 2-butynyl, 3-butynyl, 3-pentynyl, 3-hexynyl etc.), (53) a Ci-6 alkyl group (e.g., hydroxymethyl, hydroxyethyl etc.) substituted by 1 to 3 hydroxy and the like can be mentioned.
The substituent may be present at a substitutable 5 position, and the number of the substituents is 1 to 5, preferably 1 to 3.
As the Ce-14 aryl group of the optionally substituted
C6-i4 aryl group for R2, for example, phenyl, 1-naphthyl, 2naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl io and the like can be mentioned.
As the substituent that the C6_i4 aryl group optionally has, groups similar to the substituents, that the nitrogencontaining monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle for the aforementioned R1 is optionally has can be mentioned.
The number of the substituents is 1 to 5, preferably 1 to
3.
As the thienyl group of the optionally substituted thienyl group for R2, 2- or 3-thienyl can be mentioned.
As the substituent that the thienyl group optionally has, groups similar to the substituents that the nitrogencontaining monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle for the aforementioned R1 optionally has can be mentioned.
The number of the substituents is 1 to 4, preferably 1 to
3.
As the pyridyl group of the optionally substituted pyridyl group for R2, 2-, 3- or 4-pyridyl, or bipyridyl (e.g., 2,3'-bipyridin-5-yl) can be mentioned.
As the substituent that the pyridyl group optionally has, groups similar to the substituents that the nitrogencontaining monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle for the aforementioned R1 optionally has can be mentioned.
The number of the substituents is 1 to 4, preferably 1 to
2015268744 15 Dec 2015
3.
As the lower alkyl group of the optionally substituted lower alkyl group for R3 or R4, for example, C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and the like can be mentioned.
As the substituent that the lower alkyl group optionally has, (1) a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom etc.), (2) nitro, (3) cyano, (4) hydroxy, (5) Ci_s alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, fluoromethoxy etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (6) Ce-14 aryloxy (e.g., phenyloxy, naphthyloxy etc.), (7) C7-16 aralkyloxy (e.g., benzyloxy, phenethyloxy, diphenylmethyloxy,
1-naphthylmethyloxy, 2-naphthylmethyloxy, 2,2diphenylethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy, 5phenylpentyloxy etc.), (8) mercapto, (9) Ci-S alkyl thio (e.g., methylthio, di fluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4trifluorobutylthio, pentylthio, hexylthio etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (10) C6-i4 arylthio (e.g., phenylthio, naphthylthio etc.), (11) C7-16 aralkylthio (e.g., benzylthio, phenethylthio, diphenylmethylthio, 1-naphthylmethylthio, 2naphthylmethylthio, 2,2-diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentylthio etc.) (12) amino, ¢13) mono-Ci-6 alkylamino (e.g., methylamino, ethylamino etc.), (14) mono-C6-i4 arylamino (e.g., phenylamino, 1-naphthylamino, 230 naphthylamino etc.), (15) mono-C7-is aralkylamino (e.g., benzylamino etc.), (16) di-Ci_6 alkylamino (e.g., dimethyl amino, diethylamino etc.), (17) di-C6-i4 arylamino (e.g., diphenylamino etc.), (18) di-C7-i6 aralkylamino (e.g., dibenzylamino etc.), (19) formyl, (20) Ci_6 alkyl-carbonyl (e.g., acetyl, propionyl etc.), (21) C6-i4 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 217
2015268744 15 Dec 2015 naphthoyl etc.), (22) carboxyl, (23) Ci-β alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tertbutoxycarbonyl etc.), (24) Ce-n aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), ¢25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci_6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethyl carbamoyl etc.), ¢28) di-Ci-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), (29) C6-i4 aryl-carbamoyl (e.g., phenyl carbamoyl, 1naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), (30) Ci_6 io alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (31) Cs-i4 arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2naphthylsulfonyl etc.), (32) Ci-e alkylsulfinyl (e.g., methyl sulfinyl, ethylsulfinyl etc.), (33) C6-i4 arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl etc.), (34) formylamino, (35) Οι_δ alkyl-carbonylamino (e.g., acetylamino etc.), (36) Ce-14 aryl-carbonylamino (e.g., benzoylamino, naphthoyl ami no etc.), (37) Ci_6 alkoxycarbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino etc.), (38) Ci-s alkylsulfonylamino (e.g., methylsulfonylamino, ethyl sulfonyl amino etc.), (39) C6-i4 arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino, 1naphthylsulfonylamino etc.), (40) Ci_6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.), (41) C5_14 aryl-carbonyloxy (e.g., benzoyloxy, naphthyl carbon yloxy etc.), (42) Ci-6 alkoxycarbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy etc.), (43) mono-Ci-6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.), (44) di-Ci_6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy etc.), (45) C6-i4 aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (e.g., 18
2015268744 15 Dec 2015 pyrrolidin-l-yl, piperidino, piperazin-l-yl, morpholino, thiomorpholino, hexahydroazepin-l-yl etc.), (47) a 5- to 10membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (e.g., 2thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2lo benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3benzo [b] furanyl etc.), (48) C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), and (49) C3-.7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.) and the like can be mentioned.
is The number of the substituents is 1 to 3.
As the acyl group for R3 or R4, an acyl group having 1 to 20 carbon atoms, which is derived from organic carboxylic acid can be mentioned. For example, C1-7 alkanoyl groups (e.g., formyl; Ci-6 alkyl-carbonyl such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl and the like; etc.), C6_i4 aryl-carbonyl groups (e.g., benzoyl, naphthalenecarbonyl etc.), Ci-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec25 butoxycarbonyl, tert-butoxycarbonyl etc.), C6-i4 aryloxycarbonyl groups (e.g., phenoxycarbonyl group), C7-19 aralkylcarbonyl groups (e.g., phenyl-Ci_4 alkylcarbonyl such as benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl and the like, naphthyl-Cx-^ alkylcarbonyl such as benzhydrylcarbonyl, naphthylethylcarbonyl and the like, etc.), C7-19 aralkyloxy-carbonyl groups (e.g., phenyl-Ci_4 alkyloxycarbonyl such as benzyloxycarbonyl and the like, etc.), 5- or β-membered heterocycle-carbonyl group or condensed heterocycle-carbonyl groups thereof (e.g., pyrrolylcarbonyl such as 2- or 3-pyrrolylcarbonyl and the 19
2015268744 19 Feb 2016 like; pyrazolylcarbonyl such as 3-, 4- or 5-pyrazolylcarbonyl and the like; imidazolylcarbonyl such as 2-, 4- or 5imidazolylcarbonyl and the like; triazolylcarbonyl such as 1,2,3-triazol-4-ylcarbonyl, 1,2, 4-triazol-3-ylcarbonyl and the like; tetrazolylcarbonyl such as 1H- or 2H-tetrazol-5ylcarbonyl and the like; furylcarbonyl such as 2- or 3furylcarbonyl and the like; thienylcarbonyl such as 2- or 3thienylcarbonyl and the like; oxazolylcarbonyl such as 2-, 4or 5-oxazolylcarbonyl and the like; isoxazolylcarbonyl such as io 3-, 4- or 5-isoxazolylcarbonyl and the like;
oxadiazolylcarbonyl such as 1,2,3-oxadiazol-4- or 5ylcarbonyl, 1,2, 4-oxadiazol~3- or 5-ylcarbonyl, 1,2,5oxadiazol-3- or 4-ylcarbonyl, 1,3,4-oxadiazol-2-ylcarbonyl and the like; thiazolylcarbonyl such as 2-, 4- or 5is thlazolylcarbonyl and the like; isothiazolylcarbonyl such as 3-, 4- or 5-isothiazolylcarbonyl and the like; thiadiazolylcarbonyl such as l,2,3-thiadiazol-4- or 5ylcarbonyl, 1,2,4-thiadiazol-3- or 5-ylcarbonyl, 1,2,5thiadiazol-3- or 4-ylcarbonyl, 1,3, 4-thiadiazol-2-ylcarbonyl and the like; pyrrolidinylcarbonyl such as 2- or 3pyrrolidinylcarbonyl and the like; pyridylcarbonyl such as 2-, 3- or 4-pyridylcarbonyl and the like; pyridylcarbonyl wherein nitrogen atom is oxidized such as 2-, 3- or 4-pyridyl-Noxidocarbonyl and the like; pyridazinylcarbonyl such as 3- or
4-pyridazinylcarbonyl and the like; pyridazinylcarbonyl wherein one or both nitrogen atoms are oxidized, such as 3-, 4-, 5- or 6 pyridazinyl-N-oxidocarbonyl and the like; pyrimidinylcarbonyl such as 2-, 4- or 5-pyrimidinylcarbonyl and the like;
pyrimidinylcarbonyl wherein one or both nitrogen atoms are oxidized, such as 2-, 4-, 5- or 6-pyrimidinyl-N-oxidocarbonyl and the like; pyrazinylcarbonyl; piperidinylcarbonyl such as
2-, 3- or 4-piperidinylcarbonyl and the like;
piperazinylcarbonyl; indolylcarbonyl such as 3H-indol-2- or 3ylcarbonyl and the like; pyranylcarbonyl such as 2-, 3- or 435 pyranylcarbonyl and the like; thiopyranylcarbonyl such as 2-,
2015268744 15 Dec 2015
3- or 4-thiopyranylcarbonyl and the like; quinolylcarbonyl such as 3-, 4-, 5-, 6-, 7- or 8-quinolylcarbonyl and the like; isoquinolylcarbonyl; pyrido[2, 3-d]pyrimidinylcarbonyl (e.g., pyrido[2,3-d]pyrimidin-2-ylcarbonyl); naphthyridinylcarbonyl (e.g., 1,5-naphthyridin-2- or 3-ylcarbonyl) such as 1,5-, 1,6, 1,7-, 1,8-, 2,6- or 2,7-naphthyridinylcarbonyl and the like; thieno[2,3-d]pyridylcarbonyl (e.g., thieno[2,3-d]pyridin-3ylcarbonyl); pyrazinoquinolylcarbonyl (e.g., pyrazino[2,3b]quinolin-2-ylcarbonyl); a 5- or 6-membered heterocycle10 carbonyl group (e.g., chromenylcarbonyl (e.g., 2H-chromen-2or 3-ylcarbonyl etc.) and the like) containing 1 to 4 hetero atoms such as nitrogen atom (optionally oxidized), oxygen atom, sulfur atom (optionally mono or dioxidized) and the like), a 5- or 6-membered heterocycle-acetyl group (e.g., 515 or 6-membered heterocycle-acetyl group containing 1 to 4 hetero atoms such as nitrogen atom (optionally oxidized), oxygen atom, sulfur atom (optionally mono or dioxidized) and the like), such as 2-pyrrolylacetyl, 3-imidazolylacetyl, 5isoxazolylacetyl and the like, and the like can be used.
As regards the substituent of acyl group, for example, when the above-mentioned acyl group is an alkanoyl group or alkoxy-carbonyl group, the acyl group is optionally substituted by 1 to 3 alkylthio groups (e.g., C1-4 alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio and the like, and the like), halogen (e.g., fluorine, chlorine, bromine, iodine), alkoxy groups (e.g., Ci_6 alkoxy such as methoxy, ethoxy, n-propoxy, tert-butoxy, n-hexyloxy and the like, and the like), a nitro group, alkoxy-carbonyl groups (e.g., C1-6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, nbutoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tertbutoxycarbonyl and the like, and the like), alkylamino group (e.g., mono- or di-Ci-6 alkylamino such as methylamino, ethylamino, n-propylamino, n-butylamino, tert-butylamino, n35 pentylamino, n-hexylamino, dimethylamino, diethylamino,
2015268744 15 Dec 2015 methylethylamino, di-(n-propyl)amino, di-(n-butyl)amino and the like, and the like), alkoxyimino groups (e.g., Ci_6 alkoxyimino such as methoxyimino, ethoxyimino, n-propoxyimino, tert-butoxyimino, n-hexyloxy-imino and the like, and the like) or hydroxyimino.
When the above-mentioned acyl group is an aryl-carbonyl group, an aryloxy-carbonyl group, an aralkyl-carbonyl group, an aralkyloxycarbonyl group, a 5- or 6-membered heterocyclecarbonyl group or a 5- or 6-membered heterocycle-acetyl group, it is optionally substituted by 1 to 5 (preferably 1 to 3) alkyl groups (e.g., Ci_6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and the like, C3_6 cycloalkyl such as cyclohexyl and the like, and the like), alkenyl groups (e.g., C2-6 alkenyl such as allyl, isopropenyl, isobutenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl and the like, and the like), alkynyl groups (e.g., C2-6 alkynyl such as propargyl, 2-butynyl, 3-butynyl, 3-pentynyl, 3-hexynyl and the like, and the like), alkoxy groups (e.g., Ci_6 alkoxy such as methoxy, ethoxy, n-propoxy, tert-butoxy, n-hexyloxy and the like, and the like), acyl groups [e.g., Ci_7 alkanoyl such as formyl, acetyl, propionyl, butyryl,, isobutyryl, pentanoyl, hexanoyl, heptanoyl and the like; Cs-i4 aryl-carbonyl such as benzoyl, naphthalenecarbonyl and the like; Ci-s alkoxy25 carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like; Cg-i4 aryloxy-carbonyl such as phenoxycarbonyl and the like; C7-19 aralkyl-carbonyl such as phenyl-Ci-4 alkyl-carbonyl (e.g., benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl and the like) and the like; C7-19 aralkyloxy-carbonyl such as phenyl-Ci_4 alkyloxy-carbonyl (e.g., benzyloxycarbonyl and the like) and the like, and the like], nitro, amino, hydroxy, cyano, sulfamoyl, mercapto, halogen (e.g., fluorine, chlorine, bromine, iodine) , or alkylthio groups (C1-4 alkylthio such as 22
2015268744 15 Dec 2015 methylthio, ethylthio, n-propylthio, isobutylthio and the like, and the like).
As the halogen atom for R3 or R4, fluorine, chlorine, bromine and iodine can be mentioned.
As the alkyl group for R5, for example, Ci-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tert-butyl, pentyl, hexyl etc.) and the like can be mentioned.
As R1, a nitrogen-containing monocyclic heterocyclic io group optionally condensed with a benzene ring or a heterocycle (e.g., 5-6-membered aromatic nitrogen-containing monocyclic heterocyclic groups such as thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like, and the like) optionally substituted by 1 to 3 substituents selected from (i) halogen (e.g., fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) Ci_6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) Ci-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (vi) amino group optionally substituted by Ci-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.), (vii) oxo and (viii) Ci_6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tertbutoxycarbonyl etc.) is preferable.
As R1, especially, a nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle (e.g., a 5-6-membered aromatic nitrogencontaining monocyclic heterocyclic group such as thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like, and the like), which is optionally 23
2015268744 15 Dec 2015 substituted by 1 to 3 substituents selected from (i) halogen (e.g., fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) Ci_6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) Ci_6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., io fluorine, chlorine, bromine, iodine), (vi) an amino group optionally substituted by Ci~6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) and (vii) oxo, is preferable.
As R1, particularly, a 6-membered nitrogen-containing aromatic heterocyclic'group (e.g., pyridyl groups (e.g., 2-,
3- or 4-pyridyl etc.), pyrimidinyl groups (e.g., 2-, 4- or 5pyrimidinyl etc.), pyridazinyl groups (e.g., 3- or 4pyridazinyl etc.) etc.) optionally substituted by 1 to 3 substituents selected from (i) halogen (e.g., fluorine, chlorine, bromine, iodine) , (ii) hydroxy, (iii) cyano, (iv) Ci-s alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) Ci-β alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) and (vi) an amino group optionally substituted by Ci_s alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) is preferable, and a pyridyl group optionally substituted by 1 to 3 substituents selected from (i) Ci_6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen 24
2015268744 15 Dec 2015 (e.g., fluorine, chlorine, bromine, iodine) and (ii) Ci-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) is particularly preferable.
As R2, [1] a C6-i4 aryl group (e.g., phenyl group) optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom (e.g., fluorine, io chlorine, bromine, iodine), (ii) cyano, (iii) Ci_s alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine,, bromine, iodine), (iv) Ci_6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) acetyl, (vi) C3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.), (vii) Ci-g alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (viii) a Ci_6 alkyl group substituted by 1 to 3 hydroxy (e.g., hydroxymethyl, hydroxyethyl etc.), (ix) Ci-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, pentylthio, hexylthio etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and (x) Ci-6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.), [2] a thienyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) Ci_6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) Ci-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,
2015268744 15 Dec 2015 hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) and (v) acetyl, or [3] a pyridyl group optionally substituted by 1 to 4 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) lower (specifically Ci-6) alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to io 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv)
Ci-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) acyl (e.g., acetyl), (vi) nitro and (vii) amino is preferable.
Of these, as R2, [1] a C6-i4 aryl group (e.g., phenyl group) optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) Ci_6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) Ci_6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) and (v) acetyl, [2] a thienyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) Ci_6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 '(preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) Ci_6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,
2015268744 15 Dec 2015 hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) and (v) acetyl, or [3] a pyridyl group optionally substituted by 1 to 4 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) lower (specifically Cx-s) alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to io 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv)
Ci_6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g.,. fluorine, chlorine, bromine, iodine), (v) acyl (e.g., acetyl), (vi) nitro and (vii) amino is preferable.
Particularly, [1] a phenyl group optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and (ii) Ci_6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), [2] a thienyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and (ii) Cx-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertbutyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), or [3] a pyridyl group optionally substituted by 1 to 4 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and (ii) lower (specifically Ci-6) alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen 27
2015268744 15 Dec 2015 (e.g., fluorine, chlorine, bromine, iodine) is preferable.
Of those mentioned above, a preferable embodiment of R2 include [1] a phenyl group optionally substituted by 1 to 5 substituents selected from (i) a halogen atom and (ii) Ci-6 alkyl optionally substituted by 1 to 5 halogen atoms, [2] a pyridyl group optionally substituted by 1 to 4 substituents selected from lower (Ci-e) alkyl, a halogen atom, alkoxy (Ci_6 alkoxy), cyano, acyl (e.g., acetyl), nitro and amino, and the like.
io As R2, a phenyl group, a 2-fluorophenyl group, a 2methylphenyl group, a 2-fluoropyridin-3-yl group, a 3fluoropyridin-4-yl group, a 2-chloropyridin-3-yl group, a 6chloropyridin-3-yl group, a 4-methylpyridin-3-yl group, a 2methylpyridin-3-yl group, a 3-methylpyridin-2-yl group, a 215 trifluoromethylpyridin-3-yl group and a 6'-chloro-2,3'bipyridin-5-yl group are particularly preferable.
Preferably R3 and R4 are each a hydrogen atom, or one of R3 and R4 is a hydrogen atom and the other is a Ci_e alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl etc.), a Ci_6 alkyl20 carbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl etc.), a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a cyano group or a nitro group. A compound wherein both R3 and R4 are hydrogen atoms is particularly preferable.
As R5, methyl or ethyl is preferable, and methyl is particularly preferable.
The above-mentioned preferable embodiments of the substituents for R1 to R5 may be optionally combined to achieve a preferable embodiment of compound (I).
Of compounds (I), a compound wherein
R1 is a 5-6-membered aromatic nitrogen-containing monocyclic heterocyclic group (for example, thiazolyl, imidazolyl, py'razolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like) or an imidazo[1,2-a]pyrimidinyl group, which are optionally substituted by 1 to 3 substituents selected from 28
2015268744 15 Dec 2015 (i) halogen (e.g., fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) Ci_6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) Ci_6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), io (vi) amino group optionally substituted by Ci-e alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) and (vii) Ci-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tertbutoxycarbonyl etc.)/
R2 is [1] a Ce-14 aryl group (e.g., phenyl group) optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) Ci-s alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert20 butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) Ci-β alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) acetyl, (vi) C3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.), (vii) C1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (viii) a Ci-β alkyl group substituted by 1 to 3 hydroxy (e.g., hydroxymethyl, hydroxyethyl etc.), (ix) Ci-S alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, pentylthio, hexylthio etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and (x) Ci-6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.),
2015268744 15 Dec 2015 [2] a thienyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) Ci_6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) Ci-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 io to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) and (v) acetyl, [3] a pyridyl group optionally substituted by 1 to 4 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) lower (specifically Ci-β) alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv)
Ci_6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (v) acyl (e.g., acetyl), (vi) nitro and (vii) amino, or [4] a bipyridyl group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine);
R3 and R4 are each a hydrogen atom, or one of R3 and R4 is a hydrogen atom and the other is a Ci-β alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl etc.), a Ci_6 alkyl-carbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl etc.), a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a cyano group or a nitro group;
R5 is methyl or ethyl is preferable, a 'compound wherein, for example
R1 is a pyridyl group optionally substituted by 1 to 3 substituents selected from (i) Ci_6 alkyl (e.g., methyl, ethyl, 30
2015268744 15 Dec 2015 propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) and (ii) Ci-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine),
R2 is [1] a phenyl group optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen io atom (e.g., fluorine, chlorine, bromine, iodine) and (ii) Ci_e alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), [2] a thienyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and (ii) Ci-β alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertbutyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), or [3] a pyridyl group optionally substituted by 1 to 4 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and (ii) lower (specifically Ci-6) alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine),
R3 and R4 are each a hydrogen atom, and R5 is methyl is particularly preferable.
As compound (I), N-methyl-1-[5-phenyl-l-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methanamine, 1-[5-(2-fluorophenyl) 1-(pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]-N-methylmethanamine, N-methyl-1-[4-methyl-l-(pyridin-3-ylsulfonyl)-5-phenyl-lH35 pyrrol-3-yl]methaneamine, N-methyl-1-[1-(pyridin-331
2015268744 15 Dec 2015 ylsulfonyl) -5- (3-thienyl) -lH-pyrrol-3-yl]methanamine, Nmethyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]methanamine, 1-[5-(2,4-difluorophenyl)-1-(pyridin3-ylsulfonyl)-lH-pyrrol-3-yl]-N-methylmethanamine, l-{5- (25 fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3yl}-N-methylmethanamine, 1-[4-fluoro-5-phenyl-l-(pyridin-3ylsulfonyl) -lH-pyrrol-3-yl]-N-methylmethanamine, N-methyl-1[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol-3yl]methanamine, 1- [5- (2-fluoropyridin-3-yl)-1-(pyridin-310 ylsulfonyl)-lH-pyrrol-3-yl]-N-methylmethanamine or a salt thereof is particularly preferable.
As a salt of compound (I), metal salt, ammonium salt, salts with organic bases, salts with inorganic bases, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned. Preferable examples of metal salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like. Preferable examples of the salt with organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid and the like. Preferable examples of the salt with basic amino acid include a salt with arginine, ly'sin, ornithine and the like. Preferable examples of the salt with acidic amino acid include a salt with aspartic acid, glutamic acid and the like.
2015268744 15 Dec 2015
Of these, pharmaceutically acceptable salts are preferable. For example, when a compound contains an acidic functional group, inorganic salts such as alkali metal salt (e.g., sodium salt, potassium salt etc.), alkaline earth metal salt (e.g., calcium salt, magnesium salt, barium salt etc.) and the like, ammonium salt and the like; and when a compound contains a basic functional group, for example, salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, or io salts with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like can be mentioned.
Compound (I) can be produced, for example, according to the methods described in JP application No. 2005-044740, Eur. J. Org. Chem., p. 2283 (2001), J. Med. Chem., vol. 43, p. 1886 (2000), J. Pharm. Pharmacol., vol. 46, p. 740 (1994),
W092/04025, J. Heterocycl. Chem., vol. 25, p. 635 (1988), J. Med. Chem., vol. 14, p. 328 (1971), J. Med. Chem., vol. 35, p.
4195 (1992) or Tetrahedron Lett., vol. 26, p. 4047 (1985), or a method analogous thereto.
The production methods of compound (I) in the present invention are explained.
The compounds (II)-(XXIV) in the formula may form salts, and as such salts, for example, those similar to the salts of compound (I) can be mentioned.
While· the compounds obtained in respective steps can be used for the next reaction in the form of a reaction mixture or a crude product, they can also be easily isolated and purified from the reaction mixture by a known separation and purification means, such as recrystallization, distillation, chromatography and the like.
2015268744 15 Dec 2015
Figure AU2015268744B2_D0012
<ιχ) (X) da)
Compound (II) wherein R2, R3 and R4 are as defined above, and R6 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 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.
io By reacting compound (II) with a compound represented by the formula (Ilia):
II
O (Hla) wherein R11 * * * 15 is as defined for R1, or the protecting group described in Protective Groups in Organic Synthesis, 3rd Ed.
Theodora W. Greene, Peter G. M. Wuts, pp. 615-617, WileyInterscience (1999) (e.g., phenyl, 4-methylphenyl etc.), compound (IV) (each symbol in the formula is as defined above) can be produced.
2015268744 15 Dec 2015
This reaction is advantageously carried out using a solvent inert to the reaction. While the solvent is not particularly limited as long as the reaction proceeds, hydrocarbons such as benzene, toluene and the like and ethers such as tetrahydrofuran and the like, amides such as N,Ndimethylformamide, Ν,Ν-dimethylacetamide and the like, and the like or a mixed solvent thereof and the like are preferable.
Use of a base is effective for the reaction. As the base, for example, inorganic bases such as sodium hydride, io sodium hydroxide, potassium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate and the like, metal bases such as potassium ethoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,Ndimethylaniline, N-methylpiperidine, N-methyIpyrrolidine, Nmethylmorpholine and the like, and the like can be mentioned.
The amount of the base to be used is about 1 - about 10 mol, preferably about 1 - about 5 mol, per 1 mol of compound (II).
The reaction can also be carried out in the co-presence of crown ether. As the crown ether, for example, 15-crown-5ether, 18-crown-6-ether and the like can be mentioned. The amount of the crown ether to be used is about 1 - about 10 mol, preferably about 1 - about 5 mol, per 1 mol of compound (II) .
While the reaction time varies depending on the reagents and solvent to be used, it is generally about 30 min - about
24 hr, preferably about 30 min - about 8 hr.
The reaction temperature is generally about 0°C - about
100°C, preferably about 10°C - about 50°C.
Compound (V) (each symbol in the formula is as defined above) can be produced according to a method known per se, for example, the methods described in Tetrahedron Letters, vol.
2015268744 15 Dec 2015
13, p. 5337 (1972), Heterocycles, vol. 7, p. 77 (1977), Chem. Pharm. Bull., vol. 27, p. 2857 (1979), J. Org. Chem., vol. 62, p. 2649 (1997) and the like, or a method analogous thereto.
Compound (VI) (each symbol in the formula is as defined above) can be produced by reacting compound (V) with Nbromosuccinimide (NBS).
N-Bromosuccinimide (NBS) is preferably used in about one equivalent amount relative to compound (V), and the reaction is preferably carried out under an inert gas atmosphere such io as nitrogen, argon and the like.
This reaction is advantageously carried out using a solvent inert to the reaction. While the solvent is not particularly limited as long as the reaction proceeds, . solvents such as ethers (e.g., tetrahydrofuran, diethyl ether and the like), amides (e.g., Ν,Ν-dimethylformamide, N,Ndimethylacetamide and the like) and the like, a mixed solvent thereof and the like are preferable.
While the reaction time varies depending on the reagents and solvent to be used, it is generally about 30 min - about
24 hr, preferably about 5-12 hr. .
The reaction temperature is generally about -78°C to about 25°C, preferably about -78°C to about 0°C.
Addition of a base is sometimes effective for the reaction. While the base to be used is not limited as long as the reaction proceeds, an organic base such as pyridine, picoline, lutidine and the like, and the like can be mentioned. The amount of the organic base to be used is about 0.001 - about 10 equivalents, preferably about 0.001 - about 0.1 equivalent, per 1 mol of compound (V).
Compound (VII) (each symbol in the formula is as defined above) can be produced from compound (VI) according to a method similar to the method for producing compound (IV) from compound (II).
Compound (IV) (each symbol in the formula is as defined above) can also be produced by reacting compound (VII) with a . 36
2015268744 15 Dec 2015 compound represented by the formula (Villa):
/0H R—B
OH (Villa) or the formula (VUIb) :
Me
Figure AU2015268744B2_D0013
Me (Vlllb) wherein R2 is as defined above, according to the method described in Synthetic Communications, vol. 11, p. 513 (1981), or a method analogous thereto.
io Compound (IX) (each symbol in the formula is as defined above) can be produced by reducing compound (IV) with a reducing agent such as lithium aluminum hydride, diisobutyl aluminum hydride, sodium borohydride, calcium borohydride and the like. As the reducing agent, diisobutyl aluminum hydride is particularly preferable. The amount of the reducing agent to be used is about 0.75 - about 10 equivalents, preferably about 1 - about 5 equivalents, per 1 mol of compound (IV) .
This reaction is advantageously carried out using a solvent inert to the reaction. While the solvent is not particularly limited as long as the reaction proceeds, solvents such as hydrocarbons (e.g., benzene, toluene and the like) and ethers (e.g., tetrahydrofuran, diethyl ether and the like), and the like, a mixed solvent thereof and the like are preferable.
While the reaction time varies depending on the reagents and solvent to be used, it is generally about 30 min - about 24 hr, preferably about 30 min - about 8 hr.
The reaction temperature is generally about -78°C to about 100°C, preferably about -78°C to about 25°C.
2015268744 15 Dec 2015
Compound (X) (each symbol in the formula is as defined above) can be synthesized by reacting compound (IX) with an oxidant such as chromic acid-pyridine complex, pyridinium chlorochromate, manganese dioxide, sulfur trioxide-pyridine complex or tetra-n-propylammonium perruthenate and the like. As the oxidant, manganese dioxide, sulfur trioxide-pyridine complex or tetra-n-propylammonium perruthenate is preferable. The oxidation reaction can be carried out, for example, according to the method described in Synthesis, p. 639 (1994)
Compound (la) (each symbol in the formula is as defined above) can be produced by subjecting compound (X) and a compound represented by the formula (XI):
R—NHZ wherein R5 is as defined above, to a reductive amination reaction according to the methods described in Shin Jikken Kagaku Koza, Vol. 14-III, pp. 1380-1385 (Maruzen Press).
In addition, compound (la) can also be produced by the following method.
2015268744 15 Dec 2015
Figure AU2015268744B2_D0014
Figure AU2015268744B2_D0015
(XV) (XVI) (XIV)
Figure AU2015268744B2_D0016
(la)
Compound (XII) (each symbol in the formula is as defined above) can be produced from compound (VII) according to a method similar to the method for producing compound (IX) from compound (IV).
Compound (XIII) (each symbol in the formula is as defined above) can be produced from compound (XII) according to a method similar to the method for producing compound (X) from compound (IX).
io Compound (XIV) (each symbol in the formula is as defined above) can be produced from compound (XIII) according to a method similar to the method for producing compound (la) from compound (X).
Compound (XV) (each symbol in the formula is as defined above and R7 is an amino-protecting group) can be produced by protecting an amino group of compound (XIV) . As the aminoprotecting group, tert-butylcarbamate group (BOC group), benzylcarbamate group (Cbz group) and the like can be mentioned. The protection reaction can be carried out
2015268744 15 Dec 2015 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, WileyInterscience (1999) and the like.
Compound (XVI) (each symbol in the formula is as defined above) can be produced from compound (XV) according to a method similar to the method for producing compound (IV) from compound (VII).
Compound (la) (each symbol in the formula is as defined io above) can be produced by eliminating the amino-protecting group from compound (XVI) by a method known per se, for example, the method described in Protective Groups in Organic Synthesis, 3rd Ed., Theodora W. Greene, Peter G. M. Wuts,. pp. 494-653, Wiley-Interscience (1999) and the like.
is In addition, compounds (XVI) and (la) can also be produced by the following methods.
Figure AU2015268744B2_D0017
Figure AU2015268744B2_D0018
Figure AU2015268744B2_D0019
Compound (XVII) (each symbol in the formula is as defined 20 above) can be produced from compound (II) according to a method similar to the method for producing compound (IX) from compound (IV).
Compound (XVIII) (each symbol in the formula is as defined above) can be produced from compound (XVII) according to a method similar to the method for producing compound (X) from compound (IX).
2015268744 15 Dec 2015
Compound (XIX) (each symbol in the formula is as defined above) can be produced from compound (XVIII) according to a method similar to the method for producing compound (la) from compound (X).
Compound (XX) (each symbol in the formula is as defined above) can be produced from compound (XIX) according to a method similar to the method for producing compound (XV) from compound (XIV).
Compound (XVI) (each symbol in the formula is as defined io above) can be produced from compound (XX) according to a method similar to the method for producing compound (IV) from compound (II). Furthermore, compound (la) can be produced by a method similar to the aforementioned method.
In addition, compounds (XIII), (X) and (la) can also be is produced by the following methods.
Figure AU2015268744B2_D0020
Figure AU2015268744B2_D0021
(XXII) (XXIII) (Hla)
Figure AU2015268744B2_D0022
(X) (XI)
Figure AU2015268744B2_D0023
R (la) (XIII)
R2/^>j'A''R4 (XVIII)
Compound (XXI) (each symbol in the formula is as defined above) can be produced from compound (V) according to a method similar to the method for producing compound (IV) from
2015268744 15 Dec 2015 io compound (II).
Compound (XXII) (each symbol in the formula is as defined above) can be produced from compound (XXI) according to a method similar to the method for producing compound (IX) from compound (IV).
Compound (XXIII) (each symbol in the formula is as defined above) can be produced from compound (XXII) according to a method similar to the method for producing compound (X) from compound (IX).
Compound (XIII) (each symbol in the formula is as defined above) can be produced from compound (XXIII) according to a method similar to the method for producing compound (VI) from compound (V).
Compound (X) (each symbol in the formula is as defined above) can be produced from compound (XIII) according to a method similar to the method for producing compound (IV) from compound (VII), or from compound (XVIII) according to a method similar to the method for producing compound (IV) from compound (II). Furthermore, compound (la) can be produced according to a method similar to the aforementioned method.
Moreover, compound (XIII) and compound (XVIII) can also be synthesized by the following method, and compound (la) can be further produced by a method similar to the aforementioned method.
Figure AU2015268744B2_D0024
0a) (XVIII)
2015268744 15 Dec 2015
Compound (XXIV) (each symbol in the formula is as defined above) can be produced according to a method known per se, for example, the method described in J. Org. Chem., vol. 55, p.
6317 (1990) and the like, or a method analogous thereto.
Compound (XIII) (each symbol in the formula is as defined above) can be produced from compound (XXIV) according to a method similar to the method for producing compound (IV) from compound (II).
Compound (XVIII) (each symbol in the formula is as io defined above) can be produced from compound (XXIV) according to a method similar to the method for producing compound (IV) from compound (VII).
When Ru is a group other than the group represented by R1 in each compound, the compound can be converted to compound (I) after deprotection by a method known per se, for example, the method described in Protective Groups in Organic Synthesis, 3rd Ed., Theodora W. Greene, Peter G. M. Wuts, pp. 615-617, Wiley-Interscience (1999) and the like, using the formula (III) ,
R—S-CI o (III) wherein each symbol in the formula is as defined above, according to a method similar to the method for producing compound (IV) from compound (II) .
In each of the aforementioned reactions, when the starting compound has an amino group, a carboxyl group or a hydroxy group as a substituent, a protecting group generally used in peptide chemistry and the like may be introduced into these groups. In this case, by eliminating the protecting so group as necessary after the reaction, the objective compound can be obtained. Introduction and elimination of these protecting groups can be performed by a method known per se,
2015268744 15 Dec 2015 for example, the method described in Protective Groups in Organic Synthesis, 3rd Ed., Theodora W. Greene, Peter G. M. Wuts, Wiley-Interscience (1999) and the like.
Compound (I) can be isolated and purified by a known means such as phase transfer, concentration, solvent extraction, fractionation, liquid conversion, crystallization, recrystallization, chromatography and the like.
When compound (I) is obtained as a free compound, it can be converted to a desired salt by a method known per se or a io method analogous thereto; conversely, when compound (I) is obtained as a salt, it can be converted into a free form or another desired salt by a method known per se or a method analogous thereto.
Compound (I) may be used as a prodrug. The prodrug of is compound (I) means a compound which is converted to compound (I) under the physiological condition in the body by a reaction with an enzyme, gastric acid, or the like, that is, a compound which is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, and the like; a compound which is converted to compound (I) by hydrolysis with gastric acid, and the like.
The prodrug of compound (I) includes a compound wherein the amino group of compound (I) is modified with acyl, alkyl or phosphoryl (e.g., a compound wherein the amino group of compound (I) is modified with eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-l,3-dioxolen-4yl) methoxycarbonyl, 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, 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 44·
2015268744 15 Dec 2015 modified to ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2oxo-1,3-dioxolen-4-yl)methyl ester, cyclohexyloxycarbonylethyl ester or methylamide, etc.); and the like. These prodrugs can be produced from compound (I) by a method known per se.
In addition, the prodrug of compound (I) may be a compound, which is converted to compound (I) under the physiological conditions, as described in Pharmaceutical io Research and Development, Vol. 7 (Molecule Design), pp. 163198 (1990), published by Hirokawa Publishing Co.
When compound (I) contains an optical isomer, a stereoisomer, a regioisomer or a rotamer, either isomer and a .mixture of these are also encompassed in compound (I). For 15 example, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I). These isomers can be obtained as single products according to synthesis and separation methods known per se (concentration, solvent extraction, column chromatography, recrystallization, etc.).
The compound (I) may be a crystal, and both a single crystal and crystal mixtures are encompassed in compound (I). Crystals can be produced by crystallization according to crystallization methods known per se.
The compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate, both of which are encompassed in the compound (I) ·
A compound labeled with an isotope (e.g., 3H, 14C, 35S, 125I and the like) is also encompassed in the compound (I) .
Compound (I) and a prodrug thereof of the present invention (hereinafter sometimes to be abbreviated as the compound of the present invention) have a proton pump inhibitory effect and effectively suppress gastric acid secretion. In addition, since they show low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity,
2015268744 15 Dec 2015 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 expression, they are useful as pharmaceutical agents.
The compound of the present invention is useful for the treatment or prophylaxis of peptic ulcer (e.g., gastric ulcer, gastric ulcer due to postoperative stress, duodenal ulcer, io anastomotic ulcer, ulcer caused by non-steroidal antiinflammatory agents etc.); Zollinger-Ellison syndrome; gastritis; erosive esophagitis; reflux esophagitis such as erosive reflux esophagitis and the like; symptomatic gastroesophageal reflux disease (symptomatic GERD) such as non-erosive reflux disease or gastroesophageal reflux disease free of esophagitis and the like; functional dyspepsia; gastric cancer (including gastric cancer associated with promoted production of interleukin-ΐβ due to gene polymorphism of interleukin-1); stomach MALT lymphoma; gastric hyperacidity; upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress (e.g. stress caused by major surgery requiring postoperative intensive management, and cerebrovascular disorder, head trauma, multiple organ failure and extensive burn, each requiring intensive treatment) and the like; airway disorders; asthma and the like, pre-anesthetic administration, eradication of JTeiicobacter pylori or eradication assistance and the like, in mammals (e.g., human, simian, sheep, cattle, horse, dog, cat, rabbit, rat, mouse etc.)'.
As used herein, the above-mentioned reflux esophagitis and symptomatic gastroesophageal reflux disease (symptomatic GERD)) are sometimes collectively referred to simply as GERD.
The content of a compound of the present invention in the pharmaceutical composition of the present invention is about
0.01 to 100% by weight relative to the entire composition.
2015268744 15 Dec 2015
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 compound is orally administered as an anti-ulcer agent to an adult human (60 kg) . The compound of the present invention may be administered once daily or in 2 or 3 divided portions per day.
The compound of the present invention shows low toxicity io and can be appropriately administered orally or parenterally (e.g., topical, rectal, intravenous administrations and the like) as it is or as a preparation containing a pharmaceutical composition containing a pharmacologically acceptable carrier admixed according to a method known per se, such as tablets (including sugar-coated tablets and film-coated tablets), powder, granule, capsule (including soft capsule), orally disintegrating tablet, orally disintegrating film, liquid, injection, suppository, sustained-release preparation, plaster and the like. Particularly, the compound of the present invention is preferably administered as an oral preparation in the form of tablet, granule, capsule and the like.
The pharmacologically acceptable carrier that may be used to produce the pharmaceutical composition of the present invention includes various organic or inorganic carrier substances in common use as pharmaceutical materials, including excipients, lubricants, binders, disintegrants, water-soluble polymers and basic inorganic salts for solid preparations; and solvents, dissolution aids, suspending agents, isotonizing agents, buffers and soothing agents for liquid preparations and the like. Other ordinary pharmaceutical additives such as preservatives, anti-oxidants, coloring agents, sweetening agents, souring agents, bubbling agents and flavorings may also be used as necessary.
Such excipients include, for example, lactose, sucrose,
D-mannitol, starch, cornstarch, crystalline cellulose, light 47
2015268744 15 Dec 2015 silicic anhydride, titanium oxide and the like.
Such lubricants include, for example, magnesium stearate, sucrose fatty acid esters, polyethylene glycol, talc, stearic acid and the like.
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.
io Such disintegrants include (1) crosspovidone, (2) what is called super-disintegrants such as crosscarmellose sodium (FMC-Asahi Chemical) and carmellose calcium (Gotoku Yakuhin) etc, (3) carboxymethyl starch sodium (e.g., product of Matsutani 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-2pyrrolidinone homopolymer, including polyvinylpyrrolidone (PVPP) and l-vinyl-2-pyrrolidinone homopolymer, and is exemplified by Colidon CL (produced by BASF), Polyplasdon XL (produced by ISP), Polyplasdon XL-10 (produced by ISP), Polyplasdon INF-10 (produced by ISP) and the like.
Such water-soluble polymers include, for example, ethanol-soluble water-soluble polymers [e.g., cellulose derivatives such as hydroxypropyl cellulose (hereinafter also referred to as HPC) etc, polyvinylpyrrolidone and the like], ethanol-insoluble water-soluble polymers [e.g., cellulose derivatives such as hydroxypropylmethyl cellulose (hereinafter also referred to as HPMC) etc., methyl cellulose, carboxymethyl cellulose sodium and the like, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like] and the like.
Such basic inorganic salts include, for example, basic inorganic salts of sodium, potassium, magnesium and/or calcium. Preferred are basic inorganic salts of magnesium
2015268744 15 Dec 2015 and/or calcium. More preferred are basic inorganic salts of magnesium. Such basic inorganic salts of sodium include, for example, sodium carbonate, sodium hydrogencarbonate, disodium hydrogenphosphate and the like. Such basic inorganic salts of potassium include, for example, potassium carbonate, potassium hydrogencarbonate and the like. Such basic inorganic salts of magnesium include, for example, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium aluminometasilicate, magnesium silicate, magnesium io aluminate, synthetic hydrotalcite [MggAl2 (OH) 16·ΟΟ3·4Η2Ο], and aluminum magnesium hydroxide. Preferred are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like. Such basic inorganic salts of calcium include, for example, precipitated calcium carbonate, calcium is hydroxide, etc.
Such solvents include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
Such dissolution aids include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Such suspending agents include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate etc; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl 30 cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose etc., and the like.
Such isotonizing agents include, for example, glucose, D-'sorbitol, sodium chloride, glycerol, D-mannitol and the like.
Such buffers include, for example, buffer solutions of
2015268744 15 Dec 2015 phosphates, acetates, carbonates, citrates etc, and the like. Such soothing agents include, for example, benzyl alcohol and the like.
Such preservatives include, for example, p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Such antioxidants include, for example, sulfites, ascorbic acid, a~tocopherol and the like.
Such coloring agents include, for example, food colors io such as Food Color Yellow No. 5, Food Color Red No. 2, Food
Color Blue No. 2 etc.; food lake colors, red oxide and the like.
Such sweetening agents include, for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like.
Such souring agents include, for example, citric acid (citric anhydride), tartaric acid, malic acid and the like.
Such bubbling agents include, for example, sodium bicarbonate and the like.
Such flavorings may be synthetic substances or naturally occurring substances, and include, for example, lemon, lime, orange, menthol, strawberry and the like.
The compound of the present invention may be prepared as a preparation for oral administration in accordance with a commonly-known method, by, for example, compression-shaping with a carrier such as an excipient, a disintegrant, a binder, a lubricant, or the like, and subsequently coating the preparation as necessary by a commonly known method for the purpose of taste masking, enteric dissolution or sustained release. For an enteric preparation, an intermediate layer may be provided by a commonly known method between the enteric layer and the drug-containing layer for the purpose of separation of the two layers.
For preparing the compound of the present invention as an orally disintegrating tablet, available methods include, for 50
2015268744 15 Dec 2015 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 a water-soluble polymer to give a composition, which is coated with an enteric coating layer containing polyethylene glycol, further coated with an enteric coating layer containing triethyl citrate, still further coated with an enteric coating layer containing polyethylene glycol, and finally coated with io mannitol to give fine granules, which are mixed with additives and shaped.
The above-mentioned enteric coating layer includes, for example, a layer consisting of a mixture of one or more kinds from aqueous enteric polymer substrates such as cellulose is acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, methacrylic acid copolymers (e.g., Eudragit L30D-55 (trade name; produced by Rohm), Colicoat MAE30DP (trade name; produced by BASF), Polyquid PA30 (trade name; produced by San20 yo Chemical) etc.), carboxymethylethyl cellulose, shellac and the like; sustained-release substrates such as methacrylic acid copolymers (e.g., Eudragit NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name), etc.) and the like; water-soluble polymers; plasticizers such as triethyl citrate, polyethylene glycol, acetylated monoglycerides, triacetin, castor oil and the like; and the like, and the like.
The above-mentioned additive includes, for example, water-soluble sugar alcohols (e.g., sorbitol, mannitol, maltitol, reduced starch saccharides, xylitol, reduced palatinose, erythritol, etc.), crystalline cellulose (e.g., Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, Avicel RC-591 (crystalline cellulose carmellose sodium) etc.), low-substituted hydroxypropyl cellulose (e.g.,
LH-22, LH-32, LH-23, LH-33 (Shin-Etsu Chemical), mixtures 51
2015268744 15 Dec 2015 thereof etc.) and the like. Furthermore, binders, souring agents, bubbling agents, sweetening agents, flavorings, lubricants, coloring agents, stabilizers, excipients, disintegrants etc. are also used.
s The compound of the present invention may be used in combination with 1 to 3 other active ingredients.
Such other active ingredients include, for example, anti-Helicobacter pylori active substances, imidazole compounds, bismuth salts, quinolone compounds, and so forth.
Such anti-Helicobacter pylori active substances include, for example, antibiotic penicillins (e.g., amoxicillin, benzylpenicillin, piperacillin, mecillinam, ampicillin, temocillin, bacampicillin, aspoxicillin, sultamicillin, lenampicillin, etc.), antibiotic cefems (e.g., cefixime, cefaclor, etc.), antibiotic macrolides (e.g., erythromycin, clarithromycin, roxithromycin, rokitamycin, flurithromycin, telithromycin, etc.), antibiotic tetracyclines (e.g., tetracycline, minocycline, streptomycin, etc.), antibiotic aminoglycosides (e.g., gentamicin, amikacin, etc.), imipenem and so forth. Of these substances, preferred are antibiotic penicillins, antibiotic macrolides and the like.
Such imidazole compounds include, for example, metronidazole, miconazole and the like.
Such bismuth salts include, for example, bismuth acetate, bismuth citrate, bismuth subsalicylate and the like. Such quinolone compounds include, for example, ofloxacin, ciploxacin and the like.
For eradication of Helicobacter pylori, a compound (I) or a salt thereof of the present invention with antibiotic penicillin (e.g., amoxicillin and the like) and antibiotic erythromycin (e.g., clarithromycin and the like) is preferably used.
For the purpose of eradication of Helicobacter pylori, while the compound of the present invention has an anti-H.
pylori action (bacteriostatic action or eradication action) by 52
2015268744 15 Dec 2015 itself, it can enhance the antibacterial action of other antibiotics based on the pH controlling action in the stomach and the like, and also provides an assistant effect such as an eradication effect based on the action of the antibiotics to be used in combination.
Such other active ingredients and the compound (I) or a salt thereof of the present invention may be mixed, prepared as a single pharmaceutical composition [e.g., tablets, powders, granules, capsules (including soft capsules), io liquids, injectable preparations, suppositories, sustainedrelease preparations, etc.], in accordance with a commonly known method, and used in combination, and may also be prepared as separate preparations and administered to the same subject simultaneously or at a time interval.
In addition, the compound of the present invention may be used in combination with a gastric motility enhancer, a drug acting on lower esophageal sphincter (e.g., temporary lower esophageal sphincter relaxation suppressant etc.), C1C-2 channel opener (intestinal juice secretion enhancer), a histamine H2 receptor antagonist, an antacid, a sedative, a stomachic digestant or a non-steroidal anti-inflammatory drug (NSAID).
As the gastric motility enhancer, 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 optically active form thereof and the like, and the like can be mentioned.
As the C1C-2 channel opener (intestinal juice secretion enhancer), lubiprostone and the like can be mentioned.
As the histamine H2 receptor antagonist, cimetidine, ranitidine, famotidine, roxatidine, nizatidine, lafutidine and the like can be mentioned.
As the antacid, sodium hydrogencarbonate, aluminum
2015268744 15 Dec 2015 hydroxide and the like can be mentioned.
As the sedatives, diazepam, chlordiazepoxide and the like can be mentioned.
As the stomachic digestant, gentiana, swertia japonica, 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.
io A gastric motility enhancer, a drug acting on lower esophageal sphincter, a ClC-2 channel opener (intestinal juice secretion enhancer), a histamine H2 receptor antagonist, an antacid, a sedative, a stomachic digestant or a non-steroidal anti-inflammatory drug and compound (I) or a salt thereof of the present invention may be mixed, prepared as a single pharmaceutical composition [e.g., tablets, powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc.] according to a method known per se for combined use, or may also be prepared as separate preparations and administered to the same subject simultaneously or in a staggered manner.
The compound of the present invention may be used in combination with the following drugs.
(i) proton pump inhibitors, e.g., omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lansoprazole;
(ii) oral antacid mixtures, e.g., Maalox®, Aludrox® and Gaviscon®;
(iii) mucosal protective agents, e.g., polaprezinc, ecabet sodium, rebamipide, teprenone, cetraxate, sucralfate, chloropylline-copper and plaunotol;
(iv) anti-gastric agents, e.g., Anti-gastrin vaccine, itriglumide and Z-360;
(v) 5-HT3 antagonists, e.g., dolasetron, palonosetron, alosetron, azasetron, ramosetron, mitrazapine, granisetron,
2015268744 15 Dec 2015 tropisetron, E-3620, ondansetron and indisetron;
(vi) 5-HT4 agonists, e.g., tegaserod, mosapride, cinitapride and oxtriptane;
(vii) laxatives, e.g., Trifyba®, Fybogel®, Konsyl®,
Isogel®, Regulan®, Celevac® and Normacol®;
(viii) GABAs agonists, e.g., baclofen and AZD-3355;
(ix) GABAs antagonists, e.g., GAS-360 and SGS-742;
(x) calcium channel blockers, e.g., aranidipine, 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;
is (xi) dopamine antagonists, e.g., metoclopramide, domperidone and levosulpiride;
(xii) Tachykinin (NK) antagonists, particularly NK-3, NK2 and NK-1 antagonists, e.g., nepadutant, saredutant, talnetant, (aR, 9R) -7- [3,5-bis(trifluoromethyl)benzyl]20 8, 9,10, ll-tetrahydro-9-methyl-5-(4-methylphenyl)-7H[1,4]diazocino[2,1-g][1,7]naphthridine-6-13-dione (TAK-637),
5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4triazol-3-one (MK-869), lanepitant, dapitant and 3-[[225 methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenylpiperidine (2S,3S);
(xiii) nitric oxide synthase inhibitors, e.g., GW-274150, tilarginine, P54, guanidioethyldisulfide and nitroflurbiprofen;
(xiv) vanilloid receptor 1 antagonists, e.g., AMG-517 and
GW-705498;
(xv) ghrelin agonists, e.g., capromorelin and TZP-101;
(xvi) AchE release stimulants, e.g., Z-338 and KW-5092.
The above-mentioned drugs (i)-(xvi) and compound (I) or a salt thereof of the present invention may be mixed, prepared 55
2015268744 15 Dec 2015 as a single pharmaceutical composition [e.g., tablets, powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc.] according to a method known per se for combined use, or may also be prepared as separate preparations and administered to the same subject simultaneously or in a staggered manner.
Examples
The present invention is explained in detail in the io following by referring to Reference Examples, Examples and
Experimental Examples, which are not to be construed as limitative.
In the following Reference Examples and Examples, the room temperature generally means about 10°C to about 35°C, is but it is not particularly strictly limited. The mixing ratio of liquids shows a volume ratio. Unless otherwise specified, % means weight %. The yield is in mol/mol%. Silica gel column chromatography was performed using silica gel 60 (0.063-0.200 mm) manufactured by MERCK or Fuji Silysia
Chemical Ltd. Chromatorex (product name) NH (described as basic silica gel column chromatography). The melting point was measured using Yanagimoto trace melting point measurement apparatus or Buechi trace melting point measurement apparatus (B-545), and shown without amendment. For 1H-NMR spectrum, tetramethylsilane was used as the internal standard, and Varian Gemini-200 (200 MHz), Mercury-300 (300 MHz) spectrometer, Bruker AVANCE AV300 (300 MHz) and 0MM-AL400 (400 MHz) nuclear magnetic resonance apparatuses JEOL DATUM (JEOL DATUM LTD.) were used for the measurement. The following abbreviations are used for showing the measurement results, s: singlet, d: doublet, dd: double doublet, dt: double triplet, t: triplet, q: quartet, m: multiplet, br: broad, brs: broad singlet, J: coupling constant, Hz: Hertz.
Reference Example 1
2-bromo-l-(2-fluorophenyl)propan-l-one 56
2015268744 15 Dec 2015
To a solution of 2'-fluoropropiophenone (25.0 g) in acetic acid (250 mL) was slowly added bromine (8.4 mL). The mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. Water (200 mL) was added to the residue, and the mixture was extracted with diisopropyl ether. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow io oil (yield 36.8 g, 97%).
XH-NMR (CDC13)5: 1.89-1.91 (3H, m) , 5.27-5.34 (1H, m) , 7.127.19 (1H, m), 7.24-7.30 (1H, m), 7.52-7.59 (1H, m) , 7.88-7.93 (1H, m) .
Reference Example 2 ethyl 2-cyano-4-oxo-4-phenylbutanoate
Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (37 mL), and the mixture was stirred at 40-45°C for 45 min. A solution (100 mL) of phenacyl bromide (10.0 g) in acetone was added dropwise over 30 min. After completion of the dropwise addition, the mixture was stirred at room temperature for 18 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1-»1:1) to give the title compound as a pale-yellow oil (yield 10.41 g, 90%).
hi-NMR (CDC13)5: 1-35 (3H, t, J=7.2 Hz), 3.55 (1H, dd, J=16.Q, 5.6 Hz), 3.80 (1H, dd, J=16.0, 7.0 Hz), 4.16 (1H, dd, J=7.0,
5.-6 Hz), 4.31 (2H, q, J=7.2 Hz), 7.40-7.70 (3H, m) , 7.90-8.00 (2H, m) .
Example 3
2015268744 15 Dec 2015 methyl 2-cyano-4-(2-fluorophenyl)-3-methyl-4-oxobutanoate To a solution of methyl cyanoacetate (15.5 mL) and diisopropylethylamine (64 mL) in tetrahydrofuran (110 mL) was added a solution of 2-bromo-l-(2-fluorophenyl)propan-l-one (36.8 g) in tetrahydrofuran (160 mL), and the mixture was stirred at 70°C for 20 hr. The reaction mixture was allowed to cool to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography io (eluent: hexane-ethyl acetate=5:l) to give the title compound as a brown oil (yield 31.9 g, 80%).
1H-NMR (CDC13)5: 1.42-1.46 (3H, m) , 3.82-3.85 (4H, m) , 3.994.17 (1H, m), 7.14-7.22 (1H, m) , 7.25-7.31 (1H, m), 7.55-7.63 (1H, m), 7.85-7.91 (1H, m).
Reference Example 4 ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate
To a solution of 2'-fluoroacetophenone (28.6 g) in ethyl acetate (400 mL) was added copper (II) bromide (92.6 g), and the mixture was heated under reflux for 4 hr. The reaction mixture was allowed to cool to room temperature and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give crude 2-bromo-1(2-fluorophenyl)ethanone (yield 90.5 g) as an oil. Potassium carbonate (88 g) was added to ethyl cyanoacetate (168 g), and the mixture was stirred at 45°C for 1 hr. A solution (360 mL) of crude 2-bromo-l-(2-fluorophenyl)ethanone (90.5 g) in acetone was added dropwise over 20 min. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr. Water (300 mL) and ethyl acetate (300 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous sodium dihydrogen phosphate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the 58
2015268744 15 Dec 2015 residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=20:1—>4:1) to give the title compound as an oil (yield 64.0 g, about 100%).
‘'H-NMR (CDC13)5: 1.35 (3H, t, J=7.2 Hz), 3.55-3.80 (2H, m) ,
4.11 (1H, t, J=6.0 Hz), 4.24-4.34 (2H, m), 7.15-7.29 (2H, m) , 7.55-7.62 (1H, m), 7.94 (1H, dt, J=7.5, 1.8 Hz).
Reference Example 5 ethyl 2-cyano-4-oxo-4-[(2-trifluoromethyl)phenyl]butanoate
2'-(Trifluoromethyl)acetophenone (10.0 g) was dissolved in chloroform (30 mL) and diethyl ether (30 mL), a solution of bromine (8.50 g) in chloroform (20 mL) was added dropwise while maintaining the reaction temperature at not higher than 25°C. After the dropwise addition, the mixture was stirred at room temperature for 1 hr, water was added to the reaction is mixture and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentration under reduced pressure to give crude 2-bromo-l-(2-trifluoromethylphenyl)ethanone. Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (44.44 g), and the mixture was stirred at 45°C for 1 hr. A solution of crude 2-bromo-l-(2-trifluoromethylphenyl)ethanone in acetone (100 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr, and stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1_>7:1) to give the title compound as an oil (yield 10.43 g, from 2' 35 (trifluoromethyl)acetophenone, yield 66%).
2015268744 15 Dec 2015 '‘'H-NMR (CDC13)§: 1.36 (3H, t, J=7.2 Hz), 3.34-3.46 (1H, m) , 3.59-3.70 (1H, m), 4.08-4.22 (1H, m) , 4.32 (2H, q, J=7.2 Hz), 7.57-7.80 (4H, m) .
Reference Example 6 ethyl 2-chloro-5-phenyl-lH-pyrrole-3-carboxylate
To a solution (60 mL) of ethyl 2-cyano-4-oxo-4phenylbutanoate (5.0 g) in tetrahydrofuran was blown in hydrogen chloride (28 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Then, nitrogen was io blown in to remove excess hydrogen chloride. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:l) to give the title compound as a pale-yellow solid (yield 4.24 g, 79%).
2H-NMR (CDC13)5: 1-37 (3H, t, J=6.8 Hz), 4.33 (2H, q, J=6.8
Hz), 6.87 (1H, d, J=3.2 Hz), 7.20-7.60 (5H, m), 8.79 (1H, br) . Reference Example 7 ethyl 2-chloro-5-(2-fluorophenyl)-lH-pyrrole-3-carboxylate A mixture of ethyl 2-cyano-4-(2-fluorophenyl)-420 oxobutanoate (19.3 g) and 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:l->3:1) to give the title compound as a brown solid (yield 8.76 g, 53%).
1H-NMR (CDC13)5: 1.36-1.41 (3H, m) , 4.33 (2H, q, J=7.2 Hz), 6.99-7.00 (1H, m) , 7.09-7.26 (3H, m), 7.55-7.61 (1H, m), 9.08 (1H, brs).
Reference Example 8 methyl 2-chloro-5-(2-fluorophenyl)-4-methyl-lH-pyrrole-3carboxylate
To a solution of methyl 2-cyano-4-(2-fluorophenyl)-3methyl-4-oxobutanoate (31.0 g) in ethyl acetate (30 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (150 mL), and the mixture was stirred at room temperature for 2 60
2015268744 15 Dec 2015 days. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed twice with water, and then washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title, compound as white crystals (yield 19.3 g, 58%).
1H-NMR (CDC13)6: 2.33 (3H, s) , 3.86 (3H, s) , 7.12-7.42 (4H, m) , io 8.53 (1H, brs). '
Reference Example 9 ethyl 5-phenyl-lH-pyrrole-3-carboxylate
To a solution (50 mL) of ethyl 2-chloro-5-phenyl-lHpyrrole-3-carboxylate (8.5 g) in ethanol was added 10% is palladium carbon (50% containing water, 0.5 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1—»1:1) to give the title compound as a colorless solid (yield 4.50 g, 62%).
1H-NMR (CDC13)5: 1.36 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 6.91 (1H, m), 7.20-7.70 (6H, m), 8.77 (1H, br).
Reference Example 10 ethyl 5-(2-fluorophenyl)-lH-pyrrole-3-carboxylate
To a solution (80 mL) of ethyl 2-chloro-5-(2fluorophenyl)-lH-pyrrole-3-carboxylate (8.6 g) in ethanol was added 10% palladium carbon (50% containing water, 0.86 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 36 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (70 mL), 10% palladium carbon (50% containing water, 0.90 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 60 hr. The reaction mixture was filtered, and the filtrate was
2015268744 15 Dec 2015 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:l-»5:l) to give the title compound as a brown solid (yield 1.37 g, 18%).
1H-NMR (CDC13)5: 1-67 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 7.03-7.05 (1H, m) , 7.08-7.25 (3H, m), 7.49-7.50 (1H, m), 7.58-7.66 (1H, m), 9.22 (1H, brs).
Reference Example 11 methyl 5-(2-fluorophenyl)-4-methyl-lH-pyrrole-3-carboxylate io To a solution of methyl 2-chloro-5-(2-fluorophenyl)-4methyl-lH-pyrrole-3-carboxylate (10.2 g) in methanol (200 mL) was added 10% palladium carbon (50% containing water, 1.28 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 20 hr. The reaction mixture was filtered, is and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution (100 mL) was added to the residue, and the mixture was extracted with ethyl,acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound as white crystals (yield 6.70 g, 7 6%) .
^-NMR (CDC13)5: 2.40 (3H, s) , 3.82 (3H, s) , 7.12-7.33 (3H, m) ,
7.42-7.49 (2H, m), 8.67 (1H, brs).
Reference Example 12 ethyl 5-[(2-trifluoromethyl)phenyl]-lH-pyrrole-3-carboxylate By a similar operation as in Reference Examples 7 and 9 and using ethyl 2-cyano-4-oxo-4-[(230 trifluoromethyl)phenyl]butanoate, the title compound was obtained as colorless crystals. More specifically, a mixture of ethyl 2-cyano-4-[(2-trifluoromethyl)phenyl]-4-oxobutanoate (10.2 g) and 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and
2015268744 15 Dec 2015 the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:l->3:1) to give ethyl 2chloro-5-[ (2-trifluoromethyl)phenyl]-lH-pyrrole-3-carboxylate as a brown solid (yield 6.37 g, 59%). This was dissolved in ethanol (120 mL), 10% palladium carbon (50% containing water,
0.5 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column io chromatography (eluent: hexane-ethyl acetate=9:1_»1:1) to give the title compound as a colorless solid (yield 2.89 g, 51%). ^-NMR (CDC13)5: 1-36 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 6.81 (1H, s), 7.42-7.61 (5H, m), 8.69 (1H, br).
Reference Example 13 (5-phenyl-lH-pyrrol-3-yl) methanol
A solution (100 mL) of ethyl 5-phenyl-lH-pyrrole-3carboxylate (2.16 g) in tetrahydrofuran was cooled to -78°C, and a 1.5 mol/L solution (24 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min. The mixture was further stirred at -78°C for i hr, water (2 mL) was added dropwise over 2 min, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was filtered using celite and anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a pale25 red powder (yield 1.51 g, 87%).
^-NMR (DMSO-d6)5: 4.34 (2H, d, J=5.4Hz), 4.60 (1H, t, J=5.4 Hz), 6.45-6.46 (1H, m), 6.74 (1H, br) , 7.11-7.15 (1H, m), 7.31-7.35 (2H, m), 7.57-7.59 (2H, m) , 11.05 (1H, s) .
Reference Example 14 [5-(2-fluorophenyl)-4-methyl-lH-pyrrol-3-yl]methanol
By a similar operation as in Reference Example 13 and using methyl 5-(2-fluorophenyl)-4-methyl-lH-pyrrole-3carboxylate (1.63 g) and a solution (15 mL) of 1.5 mol/L diisobutylaluminum hydride in toluene, the title compound was obtained as white crystals (yield 1.18 g, 82%).
2015268744 15 Dec 2015 1H-NMR (CDC13)5: 1.30 (1H, t, J=4.8 Hz), 2.25 (3H, s) , 4.61 (2H, d, J=4.8 Hz), 6.87 (1H, d, J=3.3 Hz), 7.10-7.28 (3H, m) , 7.44-7.50 (1H, m), 8.40 (1H, brs).
Reference Example 15 5 5-pheny1-1H-pyrrο1e-3-carb aldehyde
To a solution (45 mL) of (5-phenyl-lH-pyrrol-3yl) methanol (1.51 g) in acetonitrile were added tetra-n-,' propylammonium perruthenate (0.46 g), N-methylmorpholine Noxide (2.36 g) and molecular sieves 4A powder (4.5 g) , and the io mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexaneethyl acetate=4:l-»l:l) to give the title compound as a pale25 yellow powder (yield 0.92 g, 62%).
1H-NMR (CDC13)5: 6.95 (1H, m), 7.29-7.32 (1H, m) , 7.40-7.44 (2H, m) , 7.50-7.52 (3H, m), 9.02 (1H, br), 9.84 (1H, s). Reference Example 16
5-(2-fluorophenyl)-4-methyl-lH-pyrrole-3-carbaldehyde
By a similar operation as in Reference Example 15 and using [5-(2-fluorophenyl)-4-methyl-lH-pyrrol-3-yl]methanol (1.17 g), tetra-n-propylammonium perruthenate (101 mg), Nmethylmorpholine N-oxide (1.01 g) and molecular sieves 4A powder (572 mg), the title compound was obtained as pale-pink crystals (yield 0.67 g, 58%).
1H-NMR (CDC13)5: 2.45 (3H, s) , 7.14-7.36 (3H, m) , 7.44-7.50 (2H, m), 8.82 (1H, brs), 9.92 (1H, s).
Reference Example 17
5-(2-fluorophenyl)-lH-pyrrole-3-carbaldehyde
A solution (220 mL) of ethyl 5-(2-fluorophenyl)-1Hpyrrole-3-carboxylate (11.6 g) in tetrahydrofuran was cooled to -78°C, and a 1.5 mol/L solution (100 mL) of di'isobutylaluminum hydride in toluene was added dropwise over 10 min. The mixture was stirred at -78°C for 1 hr and water (10 mL) was added dropwise over 2 min. The mixture was allowed to 64
2015268744 15 Dec 2015 warm to room temperature and the mixture was stirred for 2 hr. The reaction mixture was filtered by adding celite and anhydrous magnesium sulfate and concentrated under reduced pressure to give a pale-yellow oil (yield 8.3 g) . To a solution (220 mL) of the obtained pale-yellow oil (8.30 g) in acetonitrile were added tetra-n-propylammonium perruthenate (1.75 g), N-methylmorpholine N-oxide (13.5 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered io through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3_»1:1) to give the title compound as yellow crystals (yield 5.6 g,
60%) .
1H-NMR (CDC13)5: 7.07-7.28 (4H, m) , 7.52-7.54 (1H, m) , 7.617.67 (1H, m), 9.49 (1H, brs), 9.86 (1H, s).
Reference Example 18
5-[2-(trifluoromethyl)phenyl]-lH-pyrrole-3-carbaldehyde A solution (28 mL) of ethyl 5-[220 (trifluoromethyl)phenyl]-lH-pyrrole-3-carboxylate (1.38 g) in tetrahydro furan was cooled to -78°C, and a 1.5 mol/L solution (13 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min. The mixture was further stirred at -78°C' for 1 hr, and water (3 mL) was added dropwise over 2 min. The mixture was allowed to warm to room temperature and the mixture was further stirred for 1 hr. The reaction mixture was filtered by adding celite and anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to give a pale-yellow oil (yield 1.14 g) . The obtained oil (1.14 g) was dissolved in acetonitrile (50 mL), and tetra-n-propylammonium perruthenate (0.26 g), N-methylmorpholine N-oxide (1.32 g) and molecular sieves 4A powder (5 g) were added to this solution. The mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was 65
2015268744 15 Dec 2015 purified by silica gel column chromatography (eluent; hexaneethyl acetate=4:l_»l:l) to give the title compound as colorless crystals (yield 0.71 g, 61%).
’-H-NMR (CDC13)0: 6.79-6.81 (1H, m) , 7.46-7.78 (5H, m) , 9.13 (1H, br), 9.82 (1H, s).
Reference Example 19 methyl lH-pyrrole-3-carboxylate
To a suspension of potassium tert-butoxide (17.9 g) in tetrahydrofuran (200 mL) was added dropwise a solution of p10 toluenesulfonylmethyl isocyanide (25.2 g) and methyl acrylate (11.8 mL) in tetrahydro furan (200 mL) over 30 min. The reaction mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium is hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:l) to give the title compound as a white solid (yield 6.56 g, 41%).
1H-NMR (CDC13)5: 3.82 (3H, s), 6.15 (1H, m) , 6.75 (1H, m) , 7.43 (1H, m), 8.50 (1H, brs).
Reference Example 20 methyl 4-methyl-lH-pyrrole-3-carboxylate
By a similar operation as in Reference Example 19 and using p-toluenesulfonylmethyl isocyanide (94.6 g), methyl crotonate (48.5 g) and potassium tert-butoxide (76.7 g), the title compound was obtained as a pale-yellow solid (yield 16.8 g, 25%) .
XH-NMR (CDC13)5: 2.29 (3H, s) , 3.80 (3H, s) , 6.53-6.54 (1H, m) ,
7.36-7.38 (1H, m) , 8.25 (1H, brs).
Reference Example 21 ethyl 2-methyl-lH-pyrrole-3-carboxylate
Vinyl acetate (13.4 g) was added dropwise over 2 hr to bromine (25 g) under ice-cooling with stirring. The reaction mixture was further stirred at the same temperature for 1 hr.
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Ethyl 3-oxobutanoate (18.5 g) was added, and 25% aqueous ammonia solution (44 mL) was added dropwise over 1 hr. The reaction mixture was further stirred at room temperature for 30 min, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1_>3:1) and recrystallized from hexane to give the title compound as a io colorless solid (yield 7.56 g, 35%).
1H-NMR (CDC13)§: 1.32-1.37 (3H, m) , 2.53 (3H, s) , 4.24-4.31 (2H, m), 6.55-6.58 (2H, m), 8.13 (1H, br).
Reference Example 22 methyl 5-bromo-lH-pyrrole-3-carboxylate is A solution (30 mL) of methyl lH-pyrrole-3-carboxylate (3.06 g) in tetrahydrofuran was cooled to -78°C, Nbromosuccinimide (4.38 g) and then pyridine (3 drops) were added, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=5:l) to give the title compound as a pale-yellow solid (yield 3.08 g, 62%).
1H-NMR (CDC13)5: 3.81 (3H, s) , 6.58 (1H, m) , 7.36 (1H, m) , 8.60 (1H, brs).
Reference Example 23 methyl 5-bromo-4-methyl-lH-pyrrole-3-carboxylate
By a similar operation as in Reference Example 22 and using methyl 4-methyl-lH-pyrrole-3-carboxylate (1.0 g) and Nbromosuccinimide (1.28 g), the title compound was obtained as a pale-yellow solid (yield 489 mg, 31%).
1H-NMR (CDC13)§: 2.23 (3H, s) , 3.80 (3H, s) , 7.37 (1H, d, J=3.0 67
2015268744 15 Dec 2015
Hz), 8.40 (1H, brs).
Reference Example 24 ethyl 5-bromo-2-methyl-lH-pyrrole-3-carboxylate
To a solution of ethyl 2-methyl-lH-pyrrole-3-carboxylate (1.53 g) in tetrahydrofuran (20 mL) was added Nbromosuccinimide (1.78 g) at -78°C, and the mixture was stirred at the same temperature for 30 min. Water and diethyl ether were added to extract the reaction mixture. The extract was washed with saturated brine, dried over anhydrous magnesium io sulfate, and concentrated under reduced pressure at 5°C or below. The residue was washed with hexane to give the title compound as a colorless solid (yield 2.26 g, 97%).
1H-NMR (CDC13)5: 1.30-1.35 (3H, m) , 2.51 (3H, s) , 4.22-4.29 (2H, m), 6.50 (1H, s), 8.01 (1H, br).
Reference Example 25
2-hydroxy-5-pyrimidinesulfonic acid
Fuming sulfuric acid (containing 25% sulfur dioxide, 100 mL) was cooled to 0°C, and 2-aminopyrimidine (25 g) was gradually added over 1 hr. The mixture was heated to 180°C and stirred for 40 hr. After cooling to room temperature, the mixture was poured into ice (1 kg) . The precipitate was collected by filtration and recrystallized from water to give the title compound (yield 25.6 g, 55%).
XH-NMR (DMSO-d6)5: 6.20-7.20 (2H, m) , 8.71 (2H, s) .
Reference Example 26
2-chioro-5-pyrimidinesulfonyl chloride
A mixture of 2-hydroxy-5-pyrimidinesulfonic acid (12.8 g) and phosphorus pentachloride (37.8 g) was stirred at 180°C for 4 hr. After cooling to room temperature, toluene (200 mL) was added, and the insoluble material was filtered off. The filtrate was washed with ice water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was stood in a freezer for one day to give the title compound as a pale-yellow solid (yield
14.8 g, 96%).
2015268744 15 Dec 2015 1H-NMR (CDC13)§: 9.19 (2H, s) .
Reference Example 27 6-chloropyridazine-3-thiol
To a suspension (88 mL) of sodium hydrogensulfide (3.78
g) in ethanol was added 3,6-dichloropyridazine (5.0 g), and the mixture was refluxed for 1 hr. The solvent was evaporated under reduced pressure, and water (12.5 mL) was added. The mixture was adjusted to about pH 9 with 2 mol/L sodium hydroxide solution, and the precipitate was filtered off. The io filtrate was adjusted to about pH 2 with 6 mol/L hydrochloric acid and the precipitate was collected by filtration to give the title compound as a yellow solid (yield 4.74 g, 96%).
1H-NMR (CDC13)5: 6.99 (1H, d, J=9.6 Hz), 7.60 (1H, d, J=9.6 Hz) .
Reference Example 28
6-chloropyridazine-3-sulfonyl fluoride
To a mixture cooled to -20°C of methanol (10 mL) and water (10 mL) were added potassium hydrogenfluoride (16 g) and 6-chloropyridazine-3-thiol (2.37 g). After stirring at the same temperature for 20 min, chlorine was blown in for 30 min. Ice water (20 mL) was added and the precipitate was collected by filtration. The precipitate was extracted with ethyl acetate and water. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to allow crystallization, and the crystals were washed with hexane to give the title Compound as a gray solid (yield 1.68 g, 53%). fii-NMR (CDC13)5: 7.86-7.89 (1H, m) , 8.17-8.19 (1H, m) .
Reference Example 29 pyridin-3-ylsulfonyl chloride hydrochloride
A mixture of 3-pyridinesulfonic acid (50.0 g), phosphorus pentachloride (80.0 g) and phosphorus oxychloride (100 mL) was stirred at 120°C for 8 hr. Under a nitrogen atmosphere, the mixture was cooled to room temperature, and chloroform (dehydrated, 330 mL) was added. Hydrogen chloride was blown 69
2015268744 15 Dec 2015 in, and the precipitated crystals were collected by filtration and washed with chloroform (dehydrated) to give the title compound as a white solid (yield 54.7 g, 81%).
XH-NMR (DMSO-d6)5: 8.03-8.07 (1H, m) , 8.68 (1H, d, J=8.1 Hz),
8.87 (1H, d, J=5.7 Hz), 9.01 (1H, s).
Reference Example 30
6-methoxypyridin-3-ylsulfonyl chloride
5-Amino-2-methoxypyridine (1.24 g) was dissolved in acetic acid (8.3 mL), and the mixture was stirred under iceio cooling. Concentrated hydrochloric acid (8.3 mL) was added, and an aqueous solution (5 mL) of sodium nitrite (689 mg) was added dropwise over 15 min while keeping the inside temperature at not higher than 10°C. The reaction mixture was stirred for 10 min, and gradually added at 5°C to a mixture of is cuprous chloride (280 mg) and acetic acid (17 mL) saturated in advance with sulfur dioxide gas. The mixture was allowed to gradually warm to room temperature until the generation of gas stopped. The reaction mixture was concentrated to about 5 mL under reduced pressure, and the precipitate was collected by filtration to give the title compound (yield 1.0 g, 51%) as crude crystals. This compound was used for the next reaction without purification.
Reference Example 31 6-chloropyridin-3-ylsulfonyl chloride
Under ice-cooling, thionyl chloride (12 mL) was added dropwise over 1 hr to water (70 mL) and the mixture was stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Separately, under ice-cooling, 5 amino-2-chloropyridine (5.0 g) was added to concentrated hydrochloric acid (40 mL) and the mixture was stirred. An aqueous solution (12.5 mL) of sodium nitrite (2.88 g) was added dropwise while keeping the inside temperature at not higher than 5°C, and the mixture was further stirred for 15 min. The reaction mixture was gradually added at 5°C to the above-mentioned sulfur dioxide-containing solution added with 70
2015268744 15 Dec 2015 cuprous chloride (70 mg) . Under ice-cooling, the mixture was further stirred for 30 min. The precipitate was collected by filtration, and washed with water and ethanol to give the title compound (yield 4.79 g, 58%) .
1H-NMR (CDC13)6: 7.60-7.63 (1H, m) , 8.24-8.27 (1H, m) , 9.039.04 (1H, m).
Reference Example 32 2-chloro-3-pyridinesulfonyl chloride
Under ice-cooling, thionyl chloride (24 mL) was added io dropwise over 1 hr to water (140 mL) and the mixture was stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Separately, under ice-cooling, 3 amino-2-chloropyridine (101 g) was added to concentrated hydrochloric acid (80 mL) and the mixture was stirred. An aqueous solution (25 mL) of sodium nitrite (5.75 g) was added dropwise while keeping the inside temperature at not higher than 5°C, and the mixture was further stirred for 15 min. The reaction mixture was gradually added at 5°C to the abovementioned sulfur dioxide-containing solution added with cuprous chloride (140 mg) . Under ice-cooling, the mixture was further stirred for 30 min, and the precipitate was collected by filtration and washed with water and ethanol to give the title compound (yield 6.99 g, 42%) .
XH-NMR (CDC13)5: 7.54-7.56 (1H, m) , 8.46-8.48 (1H, m) , 8.7125 8.73 (1H, m) .
Reference Example 33 6-chloro-5-methylpyridine-3-amine
Reduced iron (793 mg) was added to an aqueous solution (25 mL) of ammonium chloride (1.27 g), and the mixture was stirred at room temperature for 5 min. A solution (10 mL) of 2-chloro-3-methyl-5-nitropyridine (816 mg) in methanol was added dropwise over 10 min. The reaction mixture was stirred at· 40°C for 20 min and at 50°C for 1.5 hr and further refluxed for 1 hr. The reaction mixture was filtered through celite, and celite was washed with methanol. Methanol was mostly 71
2015268744 15 Dec 2015 removed by concentration under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:l—>7:3) to give the title compound as a solid (yield 280 mg, 42%).
^-NMR (CDC13)5: 3.62 (2H, br) , 6.88-6.89 (1H, m) , 7.70-7.71 (1H, m) .
Reference Example 34
6-chloro-5-methylpyridine-3-sulfonyl chloride
Under ice-cooling, thionyl chloride (0.6 mL) was added dropwise over 30 min to water (3.4 mL) . The mixture was stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Separately, under ice-cooling, 6chloro-5-methylpyridine-3-amine (278 mg) was added to concentrated hydrochloric acid (6 mL) and the mixture was stirred. An aqueous solution (2 mL) of sodium nitrite (148 mg) was added dropwise while keeping the inside temperature at not higher than 5°C, and the mixture was further stirred for 15 min. The reaction mixture was gradually added at 5°C to the above-mentioned sulfur dioxide-containing solution added with · cuprous chloride (5 mg). Under ice-cooling, the mixture was further stirred for 30 min, and the precipitate was collected by filtration and washed with water to give the title compound as a pale-yellow solid (yield 271 mg, 62%).
1H-NMR (CDC13)5: 2.54 (3H, s) , 8.15 (1H, s) , 8.86 (1H, s) . Reference Example 35
2-pyridinesulfonyl chloride
Under ice-cooling, 2-mercaptopyridine (2.0 g) was added to sulfuric acid (50 mL) and the mixture was stirred. Sodium hypochlorite solution (chlorine content 5%, 126 mL) was added dropwise over 1.5 hr, and the mixture was further stirred at the same temperature for 30 min. The reaction mixture was 72
2015268744 15 Dec 2015 diluted with water (100 mL), and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a colorless oil (yield 2.45 g, 77%).
‘•H-NMR (CDC13)§: 7.69-7.71 (1H, m) , 8.06-8.14 (2H, m) , 8.838.85 (1H, m).
Reference Example 36 ethyl 1-[(2-chloro-5-pyrimidine)sulfonyl]-5-phenyl-lH-pyrrolelo 3-carboxylate
Ethyl 5-phenyl-lH-pyrrole-3-carboxylate (1.60 g) was dissolved in tetrahydrofuran (50 mL), sodium hydride (60% in oil, 446 mg) was added and' the mixture was stirred at room temperature for 15 min. 15-Crown-5 (2.24 mL) was added and the is mixture was further stirred at the same temperature for 15 min. 2-Chloro-5-pyrimidinesulfonyl chloride (2.06 g) was added and the reaction mixture was stirred at room temperature for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1—»7:3) to give the title compound as a yellow oil (yield 2.03 g, 70%).
^-NMR (CDC13)5: 1.35-1.39 (3H, m) , 4.30-4.37 (2H, m) , 6.64 (1H, s), 7.22-7.26 (2H, m), 7.37-7.51 (3H, m), 8.04 (1H, s) , 8.37 (2H, s).
Reference Example 37 ethyl 1-[(2-methyl-5-pyrimidine)sulfonyl]-5-phenyl-lH-pyrrole30 3-carboxylate
Under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (87 mg) and 2 mol/L trimethylaluminum-hexane solution (1.5 mL) were added to a solution of ethyl 1-[(2-chloro-5-pyrimidine)sulfonyl]-535 phenyl-lH-pyrrole-3-carboxylate (588 mg) in tetrahydrofuran 73
2015268744 15 Dec 2015 (20 mL) with stirring. The mixture was stirred at room temperature for 15 min and 2 mol/L trimethylaluminum-hexane solution (1 mL) was added. After stirring at the same temperature for 20 min, ice water (100 mL) and ammonium chloride (2.0 g) were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl io acetate=19:l-»l:l) to give the title compound 'as a pale-yellow oil (yield 350 mg, 63%).
^-NMR (CDC13)5: 1.34-1.39 (3H, m) , 2.77 (3H, s) , 4.29-4.36 (2H, m), 6.61 (1H, s), 7.21-7.26 (2H, m), 7.37-7.49 (3H, m) , 8.06 (1H, s), 8.41 (2H, s).
is Reference Example 38 ethyl 1-[(2-amino-5-pyrimidine)sulfonyl]-5-phenyl-lH-pyrrole3-carboxylate mol/L ammonia-methanol solution (1.0 mL) was added to a solution of ethyl 1-[(2-chloro-5-pyrimidine)sulfonyl]-520 phenyl-lH-pyrrole-3-carboxylate (392 mg) in tetrahydrofuran (10 mL) with stirring. The mixture was stirred at room temperature for 20 min, saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a colorless solid (yield 373 mg, about 100%).
1H-NMR (CDC13)5: 1.34-1.39 (3H, m) , 4.28-4.36 (2H, m) , 5.60 (2H, br), 6.59 (1H, s), 7.26-7.46 (5H, m) , 8.02-8.03 (3H, m) .
Reference Example 39 ethyl 1-(imidazo [1,2-a]pyrimidin-6-ylsulfonyl)-5-phenyl-lHpyrrole-3-carboxylate • A mixture of ethyl 1-[(2-amino-5-pyrimidine)sulfonyl]-5phenyl-lH-pyrrole-3-carboxylate (373 mg), 2-bromo-l,l35 diethoxyethane (394 mg) and acetic acid (20 mL) was stirred in 74
2015268744 15 Dec 2015 a microwave reaction apparatus at 130°C for 30 min. After cooling to room temperature, the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogenearbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:l-»ethyl acetate) to give the title compound as a brown solid (yield 157 mg, 40%).
1H-NMR (CDC13)6: 1.35-1.40 (3H, m) , 4.30-4.37 (2H, m) , 6.61 (1H, s), 7.17-7.49 (2H, m), 7.26-7.49 (4H, m), 7.94 (1H, s), 7.99 (1H, s), 8.11 (1H, s), 8.38 (1H, s).
Reference Example 40 is ethyl 5-phenyl-l-(pyridazin-3-ylsulfonyl)-lH-pyrrole-3carboxylate
Ethyl 5-phenyl-lH-pyrrole-3-carboxylate (1.06 g) was dissolved in tetrahydrofuran (30 mL), sodium hydride (60% in oil, 300 mg) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (1.52 mL) was added and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridazine-3-sulfonyl fluoride (1.28 g) was added and the reaction mixture was stirred at room temperature for 30 min. Hydrazine (1.60 g) was added and the reaction mixture was stirred at room temperature for 15 min. Saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), manganese dioxide (75% chemically treated product, 5.0 g) was added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel 75
2015268744 15 Dec 2015 column chromatography (eluent: hexane-ethyl acetate=19:1-»1:1) to give the title compound (yield 613 mg, yield 24% (containing impurity)).
‘'H-NMR (CDC13)6: 1.34-1.39 (3H, m) , 4.29-4.36 (2H, m) , 6.61 (1H, s), 7.11-7.22 (2H, m) , 7.24-7.51 (5H, m), 8.20 (1H, s),
9.28-9.30 (1H, s).
Reference Example 41 methyl 5-bromo-l-(phenylsulfonyl)-lH-pyrrole-3-carboxylate Sodium hydride (60% in oil, 1.1 g) was washed with io hexane, and suspended in Ν,Ν-dimethylformamide (50 mL) . A solution (10 mL) of methyl 5-bromo-lH-pyrrole-3-carboxylate (5.0 g) in Ν,Ν-dimethylformamide was added to the suspension at 0°C. After stirring at 0°C for 30 min, a solution of benzenesulfonyl chloride (3.3 mL) in Ν,Ν-dimethylformamide (5 mL) was added, and the reaction mixture was stirred at room temperature for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=5:l) to give the title compound as a colorless solid (yield 8.5 g, 99%).
‘‘H-NMR (CDC13)§: 3.83 (3H, s), 6.68 (1H, d, J=2.1 Hz), 7.5525 7.60 (2H, m), 7.67-7.72 (1H, m), 7.96-7.99 (2H, m), 8.08 (1H, d, J=2.1 Hz).
Reference Example 42 methyl 5-bromo-4-methyl-l-(phenylsulfonyl)-lH-pyrrole-3carboxylate
Sodium hydride (60% in oil, 202 mg) was washed with hexane and suspended in Ν,Ν-dimethylformamide (10 mL). A solution (10 mL) of methyl 5-bromo-4-methyl-lH-pyrrole-3ca'rboxylate (1.0 g) in Ν,Ν-dimethylformamide was added dropwise at -78°C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 76
2015268744 15 Dec 2015 min and added dropwise to an ice-cooled solution (10 mL) of benzenesulfonyl chloride (0.71 mL) in N,N-dimethylformamide. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound as a brown solid (yield 1.13 g, 69%).
1H-NMR (CDC13)§: 2.11 (3H, s) , 3.79 (3H, s) , 7.45-7.70 (3H, m) , 7.85-7.95 (2H, m), 8.06 (1H, s).
io Reference Example 43 ethyl 2-methyl-1-(phenylsulfonyl)-lH-pyrrole-3-carboxylate By a similar operation as in Reference Example 41 and using ethyl 2-methyl-lH-pyrrole-3-carboxylate (8.81 g), sodium hydride (60% in oil, 2.58 g) and benzenesulfonyl chloride (7.8 mL), the title compound was obtained as white crystals (yield 14.3 g, 85%).
’’H-NMR (CDC13)5: 1.31 (3H, t, J=7.2 Hz), 2.62 (3H, s) , 4.24 (2H, q, J=7.2 Hz), 6.63 (1H, d, J=3.3 Hz), 7.30 (1H, d, J=3.3 Hz), 7.51-7.57 (2H, m) , 7.62-7.68 (1H, m), 7.81-7.84 (2H, m) .
Reference Example 44 ethyl 5-bromo-2-methyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carboxylate
Ethyl 5-bromo-2-methyl-lH-pyrrole-3-carboxylate (2.26 g) was dissolved in tetrahydrofuran (100 mL), sodium hydride (60% in oil, 1.16 g) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (5.90 mL) was added and the mixture was further stirred at the same temperature for 15 min. 3-Pyridinesulfonyl chloride hydrochloride (3.13 g) was added and the reaction mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1—>7:3) to give 77
2015268744 15 Dec 2015 the title compound as a yellow oil (yield 2.31 g, 64%).
1H-NMR (CDC13)5: 1.24-1.34 (3H, m) , 2.94 (3H, s) , 4.23-4.30 (2H, m), 6.69 (1H, s), 7.51-7.55 (1H, m), 8.17-8.21 (1H, m) , 8.88-8.91 (1H, m), 9.14 (1H, m).
Reference Example 45 ethyl 2-methyl-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carboxylate
A suspension of ethyl 5-bromo-2-methyl-l-(pyridin-3ylsulfonyl)-lH-pyrrole-3-carboxylate (2.26 g), phenylboronic io acid (1.54 g), dichloro[bis(triphenylphosphine)]palladium (211 mg) and sodium carbonate (1.91 g) in 1,2-dimethoxyethane (20 mL)-water (10 mL) was stirred at 80°C for 40 min. After cooling, the reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1—>6:4) to give the title compound as a colorless oil (yield 2.39 g, about 100%).
(CDC13)5: 1.30-1.34 (3H, m) , 2.92 (3H, s) , 4.23-4.30 (2H, m), 6.59 (1H, s), 7.23-7.39 (4H, m) , 7.50-7.68 (2H, m), 8.22-8.25 (1H, m), 8.61-8.62 (1H, m), 8.75-8.77 (1H, m). Reference Example 46 [5-bromo-l-(phenylsulfonyl)-lH-pyrrol-3-yl]methanol
A solution (80 mL) of methyl 5-bromo-l-(phenylsulfonyl)lH-pyrrole-3-carboxylate (7.1 g) in tetrahydrofuran was cooled to -78°C, a 1.5 mol/L solution (42 mL) of diisobutylaluminum hydride in toluene was added dropwise over 30 min and the mixture was further stirred at -78°C for 1 hr. 1 mol/L hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract wa's washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to 78
2015268744 15 Dec 2015 give the title compound as a brown oil (yield 7.1 g, about 100%).
1H-NMR (CDC13)5: 1.62 (1H, brs), 4.51 (2H, s) , 6.33-6.34 (1H, m), 7.44-7.45 (1H, m) , 7.51-7.57 (2H, m) , 7.62-7.68 (1H, m) ,
7.93-7.97 (2H, m).
Reference Example 47 [2-methyl-l-(phenylsulfonyl)-lH-pyrrol-3-yl]methanol
By a similar operation as in Reference Example 13 and using ethyl 2-methyl-l-(phenylsulfonyl)-lH-pyrrole-310 carboxylate (8.05 g) and 1.5 mol/L diisobutylaluminum hydride toluene solution (55 mL), the title compound was obtained as white crystals (yield 6.61 g, 96%) .
^-NMR (CDC13)5: 1.37 (1H, brs), 2.29 (3H, s) , 4.42 (2H, brs), 6.29 (1H, d, J=3.6Hz), 7.30 (1H, d, J=3.6 Hz), 7.49-7.55 (2H, is m), 7.58-7.64 (1H, m), 7.78-7.81 (2H, m) .
Reference Example 48
5-bromo-l-(phenylsulfonyl)-lH-pyrrole-3-carbaldehyde
To a solution (80 mL) of [5-bromo-l-(phenylsulfonyl)-1Hpyrrol-3-yl]methanol (7.1 g) in acetonitrile were added tetra20 n-propylammonium perruthenate (0.63 g) , N-methylmorpholine Noxide hydrate (4.2 g) and molecular sieves 4A powder (3.5 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:l) to give the title compound as a colorless solid (yield 4.6 g, 71%).
XH-NMR (CDC13)§: 6.73 (1H, d, J=2.1 Hz), 7.57-7.63 (2H, m) , 7.70-7.75 (1H, m), 7.98-8.02 (2H, m), 8.10 (1H, d, J=2.1 Hz), 9;77 (1H, s).
Reference Example 49
5-bromo-4-methyl-l-(phenylsulfonyl)-lH-pyrrole-3-carbaldehyde 79
2015268744 15 Dec 2015
By a similar reaction as in Reference Example 17 and using methyl 5-bromo-4-methyl-l-(phenylsulfonyl)-lH-pyrrole-3carboxylate, the title compound was obtained as a colorless solid (1.78 g, 54%).
1H-NMR (CDC13)6: 2.14 (3H, s) , 7.50-7.62 (3H, m) , 7.91-7.96 (2H, m), 8.04 (1H, s), 9.77 (1H, s).
Reference Example 50
4-methyl-5-phenyl-ΙΗ-pyr role-3-carba1dehyde
A suspension of 5-bromo-4-methyl-l-(phenylsulfonyl)-1H10 pyrrole-3-carbaldehyde (1.78 g), phenylboronic acid (1.37 g), dichloro[bis(triphenylphosphine)]palladium (0.19 g) and sodium carbonate (1.72 g) in 1,2-dimethoxyethane (30 mL)-water (10 mL) was stirred at 100°C for 1 hr. 8 mol/L aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at 90°C for 3 hr. After cooling, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1—>1:1) , and the obtained solid was washed with hexane to give the title compound as a pale-yellow solid (yield 815 mg, 69%).
1H-NMR (CDC13)5: 2.47 (3H, s) , 7.34-7.48 (6H, m) , 8.58 (1H, br), 9.91 (1H, s).
Reference Example 51
2-methyl-l-(phenylsulfonyl)-lH-pyrrole-3-carbaldehyde
To a mixture of [2-methyl-l-(phenylsulfonyl)-lH-pyrrol-3 yl]methanol (6.35 g), dimethyl sulfoxide (50 mL) and triethylamine (25 mL) was added sulfur trioxide^pyridine complex (4.57 g), and the mixture was stirred at room temperature for 12 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous
2015268744 15 Dec 2015 sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:l) to give a white title compound (yield 5.27 g, 84%).
1H-NMR (CDC13)5: 2.62 (3H, s) , 6.65 (1H, d, J=3.6 Hz), 7.35 (1H, d, J=3.6 Hz), 7.55-7.61 (2H, m), 7.66-7.71 (1H, m), 7.857.88 (2H, m), 9.89 (1H, s).
Reference Example 52
2- methyl-lH-pyrrole-3-carbaldehyde io To a solution of 2-methyl-l-(phenylsulfonyl)-lH-pyrrole~
3- carbaldehyde (4.59 g) in tetrahydrofuran (20 mL) and methanol (5 mL) was added 8 mol/L aqueous sodium hydroxide solution (2.5 mL) at 0°C, and the reaction mixture was stirred at the same temperature for 30 min. Water was added to the is reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:l) to give the title compound as a white solid (yield 1.06 g, 54%). 1H-NMR (CDC13)§: 2.56 (3H, s) , 6.58-6.59 (1H, m) , 6.65-6.67 (1H, m), 8.52 (1H, brs), 9.89 (1H, s).
Reference Example 53
2-methyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde By a similar reaction as in Reference Example 44 and using 2-methyl-lH-pyrrole-3-carbaldehyde (1.10 g), sodium hydride (60% in oil, 1.20 g), 15-crown-5 (6.0 mL) and pyridin3-ylsulfonyl chloride hydrochloride (3.22 g), the title compound was obtained as white crystals (yield 1.10 g, 44%). 1H-NMR (CDC13)5·· 2.66 (3H, s) , 6.68 (1H, d, J=3.9 Hz), 7.34 (1H, d, J=3.9 Hz), 7.51-7.55 (1H, m), 8.09-8.13 (1H, m) , 8.898.91 (1H, m), 9.10-9.11 (1H, m) , 9.90 (1H, s) .
Reference Example 54
5-bromo-2-methyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-381
2015268744 15 Dec 2015 carbaldehyde
To a solution of 2-methyl-l-(pyridin-3-ylsulfonyl)-1Hpyrrole-3-carbaldehyde (974 mg) in Ν,Ν-dimethylformamide (10 mL) was added N-bromosuccinimide (1.17 g) at 0°C, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydroqencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and io concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:l) to give the title compound as white crystals (yield 675 mg, 53%).
1H-NMR (CDC13)5: 2.89 (3H, s) , 6.18 (1H, s), 7.53-7.57 (1H, m) ,
8.21-8.26 (1H, m) , 8.91-8.93 (1H, m), 9.17-9.18 (1H, m), 9.92 (1H, s) .
Reference Example 55
5-phenyl-l- (pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde Under an argon atmosphere, 5-phenyl-lH-pyrrole-320 carbaldehyde (342 mg) was dissolved in absolute tetrahydrofuran (20 mL) and sodium hydride (60% in oil, 240 mg) was added while stirring at room temperature. After stirring at the same temperature for 15 min, 15-crown-5 (1.21 mL) was added, and the mixture was further stirred at the same temperature for 15 min. Pyridin-3-ylsulfonyl chloride hydrochloride (642 mg) was added, and the mixture was further stirred at the same temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1—»1:1) to give the title compound as a brown solid (yield 470 mg, 75%).
XH-NMR (CDC13)8: 6.60 (1H, d, J=1.8 Hz), 7.15-7.19 (2H, m) ,
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7.25-7.37 (3H, m), 7.42-7.48 (1H, m) , 7.53-7.57 (1H, m), 8.13 (1H, d, J=1.8 Hz), 8.49-8.50 (1H, m), 8.74-8.76 (1H, m), 9.90 (1H, s).
Reference Example 56
1- [ (6-methoxypyridin-3-yl)sulfonyl]-5-phenyl-lH-pyrrole-3carbaldehyde
Under an argon atmosphere, 5-phenyl-lH-pyrrole-3carbaldehyde (171 mg) was dissolved in absolute tetrahydrofuran (20 mL), and sodium hydride (60% in oil, 200 io mg) was added at room temperature while stirring. After stirring at the same temperature for 15 min, 15-crown-5 (1.01 mL) was added, and the mixture was further stirred at the same temperature for 15 min. 6-Methoxypyridin-3-ylsulfonyl chloride (623 mg) was added, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the' residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:l-»l:l) to give the title compound as an oil (yield 59 mg, 17%).
iH-NMR (CDC13)6: 3.95 (3H, s), 6.59-6.62 (2H, m) , '7.19-7.44 (6H, m), 8.08-8.10 (2H, m), 9.88 (1H, s).
Reference Example 57
1-(6-chloropyridin-3-ylsulfonyl)-5-phenyl-lH-pyrrole-3carbaldehyde
Under an argon atmosphere, 5-phenyl-lH-pyrrole-3carbaldehyde (514 mg) was dissolved in absolute tetrahydrofuran (15 mL), and sodium hydride (60% in oil, 180 mg) was added at room temperature while stirring. After stirring at the same temperature for 15 min, 15-crown-5 (0.90 mL) was added, and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridin-3-ylsulfonyl chloride (827 mg) was added, and the mixture was further stirred at the
2015268744 15 Dec 2015 same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1—»7:3) to give the title compound as an oil (yield 762 mg, 73%) .
XH-NMR (CDC13)5: 6.62 (1H, s) , 7.19-7.49 (7H, m) , 8.09 (1H, s) , io 8.24-8.26 (1H, m), 8.90 (1H, s).
Reference Example 58
1-(2-chloropyridin-3-ylsulfonyl)-5-phenyl-lH-pyrrole-3carbaldehyde
By a reaction under similar conditions as in Reference is Example 55 and using 5-phenyl-lH-pyrrole-3-carbaldehyde (514 mg), sodium hydride (60% in oil, 180 mg), 15-crown-5 (0.90 mL) and 2-chloro-3-pyridinesulfonyl chloride (716 mg), the title compound was obtained as an amorphous form (yield 716 mg,
69%) .
XH-NMR (CDC13)5: 6.64 (1H, s) , 6.70-6.90 (1H, m) , 7.05-7.08 (2H, m), 7.15-7.18 (2H, m) , 7.26-7.32 (1H, m), 7.55-7.59 (1H, m), 8.26 (1H, s), 8.44-8.46 (1H, m), 9.94 (1H, s).
Reference Example 59
1-(2-chloropyrimidin-5-ylsulfonyl)-5-phenyl-lH-pyrrole-325 carbaldehyde
By a reaction under similar conditions as in Reference Example 55 and using 5-phenyl-lH-pyrrole-3-carbaldehyde (342 mg), sodium hydride (60% in oil, 120 mg), 15-crown-5 (0.60 mL) and 2-chloro-5-pyrimidinesulfonyl chloride (554 mg), the title compound was obtained as a yellow solid (yield 390 mg, 56%). 1H-NMR (CDC13)5: 6.68 (1H, s) , 7.22-7.26 (2H, m) , 7.39-7.52 (3H, m), 8.09 (1H, s), 8.35 (2H, s) , 9.91 (1H, s) .
Reference Example 60
1-[(6-chloro-5-methylpyridin-3-yl)sulfonyl]-5-phenyl-lH35 pyrrole-3-carbaldehyde
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By a reaction under similar conditions as in Reference Example 55 and using 5-phenyl-lH-pyrrole-3-carbaldehyde (171 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and 6-chloro-5-methylpyridine-3-sulfonyl chloride (270 mg), the title compound was obtained as a solid (yield 244 mg,
68%) .
1H-NMR (CDC13)5: 2.27 (3H, s) , 6.62 (1H, s) , 7.20-7.26 (3H, m) , 7.35-7.49 (3H, m) , 8.09 (1H, s) , 8.13 (1H, m), 9.90 (1H, s) . Reference Example 61 io 2-methyl-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carbaldehyde
A solution (15 mL) of ethyl 2-methyl-5-phenyl-l-(pyridin3-ylsulfonyl)-lH-pyrrole-3-carboxylate (980 mg) in tetrahydrofuran was cooled to -78°C, a 1.5 mol/L solution (5.3 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min., and the mixture was warmed to 0°C over 2 hr. Water (100 mL) and ethyl acetate (20 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through celite, and the organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile solution (25 mL), tetra-n-propylammonium perruthenate (93 mg), Nmethylmorpholine N-oxide hydrate (466 mg) and molecular sieves
4A powder (500 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (30 mL) was added to the residue. The mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexaneethyl acetate=19:1->1:1) to give the title compound as a yellow oil. (yield 235 mg, 27%).
1H-NMR (CDC13)§: 2.93 (3H, s) , 6.51 (1H, s) , 7.18-7.42 (6H,.m),
7.59-7.64 (1H, m) , 8.60 (1H, s), 8.77-8.79 (1H, m) , 10.03 (1H, 85
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s) .
Reference Example 62
1- [ (2-xnethyl-5-pyrlmidine) sulfonyl] -5-phenyl-lH-pyrrole-3carbaldehyde
Under a nitrogen atmosphere, a solution of ethyl 1—[ (2— methyl-5-pyrimidine)sulfonyl]-5-phenyl-lH-pyrrole-3carboxylate (280 mg) in tetrahydrofuran (20 mL) was cooled to -78°C, a 1.5 mol/L solution (3.0 mL) of diisobutylaluminum hydride in toluene was added while stirring. After stirring at io the same temperature for 15 min, the mixture was allowed to warm to -40°C over 30 min. Water (50 mL) was added, and after stirring at the same temperature for 5 min, the mixture was allowed to warm to 0°C over 10 min. Ethyl acetate (30 mL) was added, and after stirring at the same temperature for 15 min, is the mixture was stirred at room temperature for 20 min. A gellike mixture was filtered through celite, and celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 mL), manganese dioxide (75% chemically treated product, 3.0 g) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexaneethyl acetate=19:1_>1:1) to give the title compound as a paleyellow solid (yield 150 mg, 61%) .
‘’H-NMR (CDC13)5: 2.78 (3H, s) , 6.64 (1H, s) , 7.21-7.26 (2H, m) ,
7.36-7.51 (3H, m), 8.10 (1H, s), 8.40 (2H, s), 9.90 (1H, s). Reference Example 63
5-(2—fluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carbaldehyde
To a solution (96 mL) of 5-(2-fluorophenyl)-lH-pyrrole-335 carbaldehyde (475 mg) in tetrahydrofuran was added sodium 86
2015268744 15 Dec 2015 hydride (60% in oil, 503 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (2.77 g) was added dropwise and the mixture was stirred for 30 min. Pyridine-3sulfonyl chloride hydrochloride (1.35 g) was added, and the mixture was further stirred for 3 hr. The reaction mixture was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified io by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3_>2:3) and crystallized from diisopropyl ether-ethyl acetate (4:1) to give the title compound as colorless crystals (yield 680 mg, 82%) .
^U-NMR (CDC13)5·· 6.68 (1H, d, J=1.8 Hz), 6.99-7.05 (1H, m) ,
15 7.16-7.19 (2H, m) , 7.35- -7.39 (1H, m), 7.45-7.51 (1H, m), 7.69-
7.73 (1H, m), 8.14 (1H, d, J=1.8 Hz) , 8.58-8.59 (1H, m) , 8.81-
8.83 (1H, m) , 9.91 (1H, s) .
Reference Example 64
1“(pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl]-1H20 pyrrole-3-carbaldehyde
To a solution (36 mL) of 5-[2-(trifluoromethyl) phenyl]lH-pyrrole-3-carbaldehyde (240 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 201 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (1.11 g) was added dropwise and the mixture was stirred for 30 min.
Pyridine-3-sulfonyl chloride hydrochloride (537 mg) was added, and the mixture was further stirred for 3 hr. The reaction mixture was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with 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: l—>2:3) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 380 mg, about 100%).
2015268744 15 Dec 2015 fii-NMR (CDC13)§: 6.69 (1H, d, J=1.8 Hz), 7.34-7.38 (1H, m) , 7.44-7.48 (1H, m), 7.61-7.69 (4H, m) , 8.16 (1H, d, J=1.8 Hz), 8.45 (1H, d, J=2.4 Hz), 8.81 (1H, m), 9.91 (1H, s).
Reference Example 65
4-methyl-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carbaldehyde
4-Methyl-5-phenyl-lH-pyrrole-3-carbaldehyde (185 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 60 mg) was added and the mixture was stirred at room io temperature for 15 min. 15-Crown-5 (0.30 mL) was added and the mixture was further stirred at the same temperature for 15 min. 3-Pyridinesulfonyl chloride hydrochloride (231 mg) was added and the reaction mixture was stirred at room temperature for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1_»1:1) to give the title compound as a colorless solid (yield 172 mg, 53%).
1H-NMR (CDC13)§: 2.03 (3H, s) , 7.01-7.04 (2H, m) , 7.26-7.55 (5H, m), 8.07 (1H, s), 8.47 (1H, m), 8.75-8.78 (1H, m) , 9.97 (1H, s) .
Reference Example 66
4-methyl-5-phenyl-l-(pyridin-2-ylsulfonyl)-lH-pyrrole-3carbaldehyde
By a reaction under similar conditions as in Reference Example 65 and using 4-methyl-5-phenyl-lH-pyrrole-3carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 1530 crown-5 (0.30 mL) and 2-pyridinesulfonyl chloride (231 mg) instead of 3-pyridinesulfonyl chloride hydrochloride, the title compound was obtained as an amorphous form (yield 262 mg,.80%).
1H-NMR (CDC13)5: 2.03 (3H, s), 6.92-6.95 (2H, m) , 7.21-7.49 (5H, m), 7.65-7.69 (1H, m), 8.14 (1H, s), 8.64-8.65 (1H, m),
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9.98 (1H, s).
Reference Example 67
1-[(l,2-dimethyl-lH-imidazol-4-yl)sulfonyl]-4-methyl-5-phenyllH-pyrrole-3-carbaldehyde
By a reaction under similar conditions as in Reference
Example 65 and using 4-methyl-5-phenyl-lH-pyrrole-3carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15crown-5 (0.30 mL) and (1,2-dimethyl-lH-imidazol-4-yl)sulfonyl chloride (253 mg), the title compound was obtained as a io colorless solid (yield 294 mg, 86%).
^-NMR (CDC13)5: 2.05 (3H, s) , 2.33 (3H, s), 3.40 (3H, s) , 6.48 (1H, s), 7.11-7.14 (2H, m), 7.26-7.41 (3H, m), 8.08 (1H, s), 9.93 (1H, s).
Reference Example 68 is 1-[(5-chloro-l,3-dimethyl-lH-pyrazol-4-yl)sulfonyl]-4-methyl5-phenyl-lH-pyrrole-3-carbaldehyde
By a reaction under similar conditions as in Reference Example 65 and using 4-methyl-5-phenyl-lH-pyrrole-3carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 1520 crown-5 (0.30 mL) and (5-chloro-l,3-dimethyl-lH-pyrazol-4yl)sulfonyl chloride (298 mg), the title compound was obtained as an oil (yield 379 mg, about 100%) .
•‘•H-NMR (CDC13)5: 1-74 (3H, s) , 2.04 (3H, s), 3.69 (3H, s) , 7.04-7.07 (2H, m) , 7.28-7.38 (3H, m), 8.09 (1H, s), 9.96 (1H,
s) .
Reference Example 69
1-[(2, 4-dimethyl-l,3-thiazol-5-yl)sulfonyl]-4-methyl-5-phenyllH-pyrrole-3-carbaldehyde
By a reaction under similar conditions as in Reference
Example 65 and using 4-methyl-5-phenyl-lH-pyrrole-3carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15crown-5 (0.30 mL) and (2,4-dimethyl-l,3-thiazol-5-yl)sulfonyl chloride (275 mg), the title compound was obtained as an oil (yield 27.8 mg, 8%).
1H-NMR (CDC13)§: 2.05 (3H, s) , 2.10 (3H, s), 2.59 (3H, s) ,
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7.07-7.10 (2H, m), 7.31-7.40 (3H, m) , 8.02 (1H, s), 9.96 (1H, s) .
Reference Example 70
5-(2-fluorophenyl)-4-methyl-l-(pyridin-3-ylsulfonyl) -1H5 pyrrole-3-carbaldehyde
By a similar operation as in Reference Example 65 and using 5-(2-fluorophenyl)-4-methyl-lH-pyrrole-3-carbaldehyde (301 mg), sodium hydride (60% in oil, 179 mg), 15-crown-5 (0.88 mL) and pyridin-3-ylsulfonyl chloride hydrochloride (476 mg), the title compound was obtained as white crystals (yield 440 mg, 87%).
XH-NMR (CDC13)5: 2.02 (3H, s), 6.98-7.04 (1H, m) , 7.13-7.24 (2H, m), 7.33-7.38 (1H, m), 7.43-7.51 (1H, m) , 7.65-7.69 (1H, m), 8.09 (1H, s), 8.54-8.55 (1H, m) , 8.80-8.82 (1H, m), 9.98 (1H, s) . '
Reference Example 71
1- [5-bromo-l-(phenylsulfonyl) -lH-pyrrol-3-yl]-Nmethylmethanamine
To a solution (60 mL) of 5-bromo-l-(phenylsulfonyl)-1H20 pyrrole-3-carbaldehyde (3.5 g) in methanol were added methylammonium chloride (7.5 g) and sodium cyanoborohydride (2.4 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil (yield 4.4 g, about 100%).
^-NMR (CDC13)5: 2.47 (3H, s) , 2.98 (1H, brs) , 3.66 (2H, s) , 6.35 (1H, d, J=2.4 Hz), 7.51-7.57 (3H, m), 7.61-7.68 (1H, m), 7.93-7.97 (2H, m).
Reference Example 72 tert-butyl {[5-bromo-l-(phenylsulfonyl)-lH-pyrrol-390
2015268744 15 Dec 2015 yl]methyl}methylcarbamate
To a solution of 1-[5-bromo-l-(phenylsulfonyl)-lH-pyrrol3-yl]-N-methylmethanamine (4.4 g) in ethyl acetate (60 mL) was added di-tert-butyl bicarbonate (2.8 mL), and the mixture was stirred at room temperature for 14 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium io sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:l) to give the title compound as a colorless oil (yield 3.4 g, 73%).
4i-NMR (CDC13)5: 1.48 (9H, s), 2.79 (3H, brs), 4.17 (2H, brs),
6.24 (1H, brs), 7.35 (1H, brs), 7.51-7.57 (2H, m), 7.62-7.68 (1H, m), 7.90-7.94 (2H, m).
Reference Example 73 tert-butyl [(5-bromo-lH-pyrrol-3-yl)methyl]methylcarbamate tert-Butyl {[5-bromo-l-(phenylsulfonyl)-ΙΗ-pyrro1-320 yl]methylJmethylcarbamate (1.0 g) was dissolved in a mixed solvent of tetrahydrofuran (15 mL) and methanol (5 mL), and 8 mol/L aqueous sodium hydroxide solution (1.5 mL) was added dropwise at not more than 10°C. After stirring at the same temperature for 4 hr, water was added to the residue and the ' mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=9:1—>4:1) to give the title compound as a pale-yellow oil (yield 410 mg, 61%).
1H-NMR (CDC13)§: 1.48 (9H, s) , 2.79 (3H, s), 4.17 (2H, s) , 6.09 (1H, brs), 6.64 (1H, brs), 8.07 (1H, br).
Reference Example 74 tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-335 yl]methyl}methylcarbamate
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To a suspension (10 mL) of sodium hydride (60% in oil, 204 mg) in tetrahydrofuran was added a solution (3 mL) of tert-butyl [(5-bromo-lH-pyrrol-3-yl)methyl]methylcarbamate (410 mg) in Ν,Ν-dimethylformamide at 0°C, and 15-crown-5 (938 mg) and pyridin-3-ylsulfonyl chloride hydrochloride (456 mg) were added at the same temperature. After stirring at room temperature for 2 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate io solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:l_>3:1) to give the title compound as a pale-yellow powder (yield 522 mg, 85%).
1H-NMR (CDC13)5: 1-47 (9H, s) , 2.80 (3H, brs) , 4.18 (2H, brs) , 6.28 (1H, brs), 7.35 (1H, brs), 7.48-7.52 (1H, m), 8.18-8.22 (1H, m) , 8.85-8.88 (1H, m) , 9.12-9.13 (1H, m).
Reference Example 75 tert-butyl {[1-(2-chloro-3-pyridinesulfonyl)-5-phenyl-lH20 pyrrol-3-ylJmethyl}methylcarbamate
1-(2-Chloro-3-pyridinesulfonyl)-5-phenyl-lH-pyrrole-3carbaldehyde (443 mg) was dissolved in absolute tetrahydrofuran (5 mL), a 2 mol/L solution (0.74 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a solution of sodium borohydride (97 mg) in methanol (2.5 mL), and the mixture was stirred at the same temperature for 20 min. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), di-tert-butyl bicarbonate (1.40 g), sodium hydrogencarbonate (0.54 g) and water (13 mL) were added, and the mixture was stirred at room 92
2015268744 15 Dec 2015 temperature for 20 min. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexaneethyl acetate=19: l—>3:1) to give the title compound as a solid (yield 361 mg, 61%).
•’•H-NMR (CDC13)5: 1-47 (9H, s) , 2.87 (3H, s) , 4.29 (2H, s) , io 6.30-6.32 (1H, m) , 6.95-7.00 (1H, m), 7.06-7.33 (5H, m), 7.517.56 (2H, m), 8.38-8.41 (1H, m).
Reference Example 76 tert-butyl {[l-(6-chloro-5-methyl-3-pyridinesulfonyl)-5phenyl-lH-pyrrol-3-yl]methylJmethylcarbamate
1-[(6-Chloro-5-methylpyridin-3-yl)sulfonyl]-5-phenyl-lHpyrrole-3-carbaldehyde (244 mg) was dissolved in absolute tetrahydrofuran (6.8 mL), a 2 mol/L solution (0.34 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was added to a solution of sodium borohydride (51 mg) in methanol (3 mL), and the mixture was stirred at the same temperature for 3 min. di-tert-Butyl bicarbonate (654 mg) was added, and water (5 mL) and sodium hydrogencarbonate (420 mg) were added 3 min later. The mixture was further stirred at room temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1_>3:1) to give the title compound as an oil (yield 247 mg, 77%).
•’’H-NMR (CDC13)§: 1.47 (9H, s) , 2.28 (3H, s) , 2.82 (3H, s) , 4.24-4.28 (2H, m), 6.15 (1H, s), 7.23-7.42 (7H, m), 8.15 (1H, s) .
Reference Example 77
2015268744 15 Dec 2015 tert-butyl ({[1-(6-chloropyridin-3-yl)sulfonyl]-5-phenyl-lHpyrrol-3-yl }methyl) methylcarbamate
1-[(6-Chloropyridin-3-yl)sulfonyl]-5-phenyl-lH-pyrrole-3carbaldehyde (1.27 g) was dissolved in absolute tetrahydrofuran (20 mL), a 2 mol/L solution (2.1 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a solution of sodium borohydride (277 mg) in methanol (10 mL), and the mixture was stirred at the same io temperature for 20 min. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate. di-tert-Butyl bicarbonate (3.99 g) was added, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), sodium hydrogencarbonate (1.53 g) and water (36 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1_>3:1) to give the title compound as a solid (yield
544 mg, 32%) .
1H-NMR (CDC13)5: 1.47 (9H, s) , 2.82 (3H, s) , 4.23 (2H, s) , 6.16 (1H, s), 7.23-7.49 (8H, m), 8.28 (1H, s) .
Reference Example 78 tert-butyl methyl ({[1- (6-methylpyridin-3-yl)sulfonyl]-530 phenyl-lH-pyrrol-3-yl}methyl) carbamate
Under an argon atmosphere, a mixture of tert-butyl ({[1— (6-chloropyridin-3-yl) sulfonyl]-5-phenyl-lH-pyrrol-3yljmethyl)methylcarbamate (100 mg), methylboronic acid (14 mg), tetrakis(triphenylphosphine)palladium (25 mg), potassium carbonate (90 mg) and dioxane (3 mL) was stirred at 80°C for 24 94
2015268744 15 Dec 2015 hr. Methylboronic acid (14 mg) and tetrakis(triphenylphosphine)palladium (25 mg) were added, and the mixture was stirred at 90°C for 24 hr. Methylboronic acid (14 mg), tetrakis(triphenylphosphine)palladium (25 mg), potassium carbonate (90 mg) and dioxane (2 mL) were added, and the mixture was stirred at 90°C for 24 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium io sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:l—>1:1) to give the title compound as an oil (yield 85.8 mg, 36%).
1H-NMR (CDC13)5: 1.46 (9H, s) , 2.58 (3H, s) , 2.81 (3H, s) ,
4.20-4.23 (2H, m), 6.13 (1H, s), 7.07-7.10 (1H, m), 7.24-7.42 (7H, m) , 8.39 (1H, s) .
Reference Example 79 tert-butyl methyl][1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-1Hpyrrol-3-yl]methyl}carbamate
Under an argon atmosphere, a suspension of tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-3yl]methylJmethylcarbamate (232 mg), 3-thienylboronic acid (138 mg), tetrakis(triphenylphosphine)palladium (31.3 mg) and sodium carbonate (175 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was stirred at 105°C for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l:l) to give the title compound as a pale-yellow oil (yield 189 mg,
81%) .
1H-NMR (CDC13)6: 1.47 (9H, s) , 2.82 (3H, brs), 4.22 (2H, brs),
2015268744 15 Dec 2015
6.17 (1H, brs) , 7.04-7.06 (1H, m) , 7.16-7.17 (1H, m) , 7.25-
7.32 (3H, m), 7 .57-7.61 (1H, m), 8. .56 (1H, d, J=2 .4 Hz), 8.71
8.73 (1H, m) .
Reference Example 80 tert-butyl {[5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]methylJmethylcarbamate
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]methylJmethylcarbamate (300 mg), (4-fluorophenyl)boronic io acid (195 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 293 mg, 94%).
’H-NMR (CDC13)6: 1-47 (9H, s) , 2.81 (3H, brs) , 4.22 (2H, brs) , 6.12 (1H, brs), 7.00-7.06 (2H, m), 7.18-7.31 (4H, m), 7.5625 7.60 (1H, m), 8.54-8.55 (1H, m) , 8.73-8.75 (1H, m) .
Reference Example 81 tert-butyl methyl{[5-(2-methylphenyl)-1-(pyridin-3ylsulfonyl) -lH-pyrrol-3-yl] methyl} carbamate
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]methylJmethylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 210 mg, 68%) . More specifically, a suspension of tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105°C for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced 96
2015268744 15 Dec 2015 pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:l-»3:1) to give the title compound as a pale-yellow oil (yield 210 mg, 68%).
1H-NMR (CE iCl3)5: 1-47 (9H, s), , 1.92 (3H, s), 2.84 (3H, brs),
4.26 (2H, brs), 6.07 (1H, d, J=1.2 Hz), 6.87-6.89 (1H, m),
7.09-7.19 (2H, m), 7. ,26-7.35 (3H, m) , 7. ,58-7.62 (1H, m), 8.54
8.55 (1H, m), 8.75-8. .77 (1H, m) .
Reference Example 82
tert-butyl {[5- (4-fluoro-2-methylphenyl)-1-(pyridin-310 ylsulfonyl)-lH-pyrrol-3-yl]methylJmethylcarbamate
By a similar operation as in Reference Example 79 and using tert-butyl { [5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]methylJmethylcarbamate (300 mg), (4-fluoro-2methylphenyl)boronic acid (215 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a paleyellow oil (yield 216 mg, 67%).
1H-NMR (CDC13)5: 1-47 (9H, s) , 1.92 (3H, s) , 2.84 (3H, brs), 4.25 (2H, brs), 6.05 (1H, br), 6.79-6.91 (3H, m) , 7.30-7.35 (2H, m), 7.61-7.65 (1H, m), 8.58-8.59 (1H, m), 8.77-8.79 (1H,
m) .
Reference Example 83 tert-butyl methyl { [5-(4-methyl-3-thienyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methyl}carbamate
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl] methyl} methyl carbamate (300 mg) , (4-methyl-3thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a paleyellow oil (yield 200 mg, 64%) . More specifically, a suspension of tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium 97
2015268744 15 Dec 2015 carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105°C for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1_>3:1) to give io the title compound as a pale-yellow oil (yield 200 mg, 64%). 1H-NMR (CDC13)5: 1.47 (9H, s) , 1.81 (3H, s) , 2.83 (3H, brs) , 4.26 (2H, brs), 6.10 (1H, br), 6.90 (1H, br), 7.02-7.03 (1H, m), 7.26-7.35 (2H, m) , 7.61-7.65 (1H, m), 8.58-8.59 (1H, m), 8.75-8.77 (1H, m).
Reference Example 84 tert-butyl {[5-(3-cyanophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]methyl}methylcarbamate
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-IH-pyrrol20 3-yl]methyl}methylcarbamate (300 mg), (3-cyanophenyl)boronic acid (205 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 298 mg, 94%) .
XH-NMR (CDC13)5: 1.47 (9H, s) , 2.81 (3H, brs), 4.22 (2H, brs),
6.21 (1H, br), 7.31-7.35 (2H, m), 7.46-7.69 (6H, m), 8.56 (1H, d, J=1.8 Hz), 8.76-8.78 (1H, m) .
Reference Example 85 tert-butyl {[5-(2-chlorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl ] methyl }methylcarbamat e
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]methyl}methylcarbamate (300 mg), (2-chlorophenyl)boronic acid (218 mg), tetrakis (triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-blue oil (yield 171 mg, 53%) .
2015268744 15 Dec 2015 1H-NMR (CDC13)§: 1-47 (9H, s) , 2.84 (3H, brs), 4.26 (2H, brs), 6.20 (1H, d, J=1.8 Hz), 7.26-7.36 (6H, m), 7.65-7.71 (1H, m) , 8.58-8.59 (1H, m), 8.75-8.79 (1H, m) .
Reference Example 86 tert-butyl {[5-(2,4-difluorophenyl)-lH-pyrrol-3y1]methy1} methyl carbamat e
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]methyl}methylcarbamate (300 mg), (2,410 difluorophenyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 113 mg, 50%) .
1H-NMR (CDC13)5: 1-50 (9H, s) , 2.84 (3H, brs), 4.30 (2H, brs),
6.49 (1H, br), 6.78-6.92 (3H, m) , 7.48-7.58 (1H, m) , 8.78 (1H, br) .
Reference Example 87 tert-butyl {[5-(2, 5-difluorophenyl)-lH-pyrrol-3yl]methylJmethylcarbamate
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]methyl}methylcarbamate (300 mg), (2,5difluorophenyl)boronic acid (220 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 135 mg, 60%).
^-NMR (CDC13)5: 1.50 (9H, s) , 2.84 (3H, brs), 4.30 (2H, brs), 6.56 (1H, br), 6.77-6.85 (2H, m), 7.00-7.08 (1H, m), 7.20-7.26 (1H, m), 8.90 (1H, br).
Reference Example 88 tert-butyl {[5-(4-chloro-2-fluorophenyl)-lH-pyrrol-3yl]methylJmethylcarbamate
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-IH-pyrrol35 3-yl]methylJmethylcarbamate (300 mg), (4-chloro-299
2015268744 15 Dec 2015 fluorophenyl)boronic acid (243 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 127 mg, 54%).
1H-NMR (CDC13)5: 1-50 (9H, s) , 2.84 (3H, s) , 4.30 (2H, s) , 6.55 (1H, br), 6.80 (1H, br), 7.11-7.15 (2H, m), 7.46-7.52 (1H, m) , 8.82 (1H, br).
Reference Example 89 tert-butyl {[5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)i o ΙΗ-py r r ο 1 - 3 - y 1 ] methyl} methyl ca rbama t e
By a similar operation as in Reference Example 44 and using tert-butyl {[5-(2,4-difluorophenyl)-lH-pyrrol-3yl]methyl}methylcarbamate (113 mg), sodium hydride (60% in oil, 51 mg), 15-crown-5 (0.21 mL) and pyridine-3-ylsulfonyl chloride hydrochloride (113 mg), the title compound was obtained as a pale-yellow oil (yield 110 mg, 68%).
1H-NMR (CDC13)5: 1.46 (9H, s) , 2.82 (3H, brs), 4.24 (2H, brs), 6.19 (1H, br), 6.77-6.92 (2H, m) , 7.11-7.19 (1H, m), 7.33-7.37 (2H, m), 7.68-7.72 (1H, m), 8.62 (1H, d, J=2.4 Hz), 8.77-8.79 (1H, m) .
Reference Example 90 tert-butyl {[5-(2,5-difluorophenyl)-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl] methyl}methylcarbamate
By a similar operation as in Reference Example 44 and using tert-butyl {[5-(2,5-difluorophenyl)-ΙΗ-pyrrol-3yl]methyl}methylcarbamate (135 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.25 mL) and pyridin-3-ylsulfonyl chloride hydrochloride (135 mg), the title compound was obtained as a colorless oil (yield 105 mg, 54%) .
1H-NMR (CDC13)§: 1.50 (9H, s) , 2.82 (3H, s), 4.23 (2H, brs), 6.24 (1H, br), 6.89-7.13 (4H, m), 7.33-7.39 (2H, m) , 7.71-7.75 (1H, m), 8.67 (1H, d, J=2.4 Hz), 8.78-8.80 (1H, m).
Reference Example 91 tert-butyl {[5-(4-chloro-2-fluorophenyl)-1-(pyridin-335 ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate 100
2015268744 15 Dec 2015
By a similar operation as in Reference Example 44 and using tert-butyl {[5-(4-chloro-2-fluorophenyl)-lH-pyrrol-3yl]methyl}methylcarbamate (127 mg), sodium hydride (60% in oil, 54 mg), 15-crown-5 (0.22 mL) and pyridin-3-ylsulfonyl chloride hydrochloride (120 mg), the title compound was obtained as a colorless oil (yield 103 mg, 57%).
H-NMR (CDC13)5: 1.46 (9H, s) , 2.81 (3H, s) , 4.23 (2H, brs), 6.21 (1H, brs), 7.08-7.15 (4H, m), 7.32-7.38 (2H, m), 7.697.73 (1H, m), 8.64 (1H, d, J=2.4 Hz), 8.77-8.79 (1H, m) .
io Reference Example 92 tert-butyl {[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl ] methyl Jmethylcarbamat e
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol15 3-yl]methyl}methylcarbamate (300 mg), (3-fluorophenyl)boronic acid (195 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 280 mg, 90%) .
Ή-NMR (CDC13)§: 1.47 (9H, s) , 2.81 (3H, brs), 4.22 (2H, brs),
6.16 (1H, brs), 6.93-7.11 (3H, m), 7.27-7.32 (3H, m) , 7.597.63 (1H, m), 8.58 (1H, d, J=2.1 Hz), 8.73-8.75 (1H, m). Reference Example 93 tert-butyl {[5-bromo-2-methyl-l-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]methyl}methylcarbamate
5-Bromo-2-methyl-l-(pyrldin-3-ylsulfonyl)-lH-pyrrole-3carbaldehyde (565 mg) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), a 40% solution (1.5 mL) of methylamine methanol was added at room temperature and the mixture was stirred for 30 min. Sodium borohydride (130 mg) was added to the reaction mixture at room temperature and the mixture was stirred for 15 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate 101
2015268744 15 Dec 2015 solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (6 mL), di-tert-butyl bicarbonate (0.45 mL) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1 mol/L hydrochloric acid (10 mL), and the mixture was further stirred for 15 min. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. io The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:l-»l:l) to give a mixture of the title compound and 5-bromo-2-methyl1-(pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde. The mixture was dissolved in tetrahydrofuran (5 mL), a 2 mol/L solution (4 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 12 hr. To the reaction mixture was added a solution of sodium borohydride (131 mg) in methanol (1 mL), and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (6 mL), di-tert-butyl bicarbonate (0.45 mL) was added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous
102
2015268744 15 Dec 2015 sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:l) to give the title compound as a yellow oil (yield 384 mg, 50%).
•‘-H-NMR (CDC13)5: 1.46 (9H, s) , 2.49 (3H, s) , 2.71 (3H, brs) , 4.15 (2H, brs), 6.24 (1H, brs), 7.47-7.52 (1H, m), 8.13-8.17 (1H, m), 8.84-8.86 (1H, m), 9.07-9.08 (1H, m) .
Reference Example 94
2-bromo-l-(2,6-difluorophenyl)ethanone io To a solution of 1-(2,6-difluorophenyl)ethanone (10.0 g) in diethyl ether (50 mL) was added anhydrous aluminum chloride (8 6 mg) and the mixture was stirred for 5 min. Bromine (3.3 mL) was added dropwise at 10-15°C. After stirring at room temperature for 2 hr, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 15.2 g, about 100%) .
1H-NMR (CDC13)5: 4.37 (2H, s) , 6.97-7.04 (2H, m) , 7.43-7.53 (1H, m).
Reference Example 95 ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate
To a solution of ethyl cyanoacetate (7.24 g) and diisopropylethylamine (19.9 g) in tetrahydrofuran (30 mL) was added dropwise a solution of 2-bromo-l-(2,6difluorophenyl)ethanone (15.16 g) in tetrahydrofuran (15 mL) at 10-15°C. The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water, 1 mol/L hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1_>3:2) 103
2015268744 15 Dec 2015 to give the title compound as a pale-green oil (yield 13.8 g, 81%) .
XH-NMR (CDC13)5: 1-35 (3H, t, J=7.1 Hz), 3.44-3.53 (1H, m) , 3.63-3.72 (1H, m) , 4.13-4.18 (1H, m), 4.31 (2H, q, J=7.1 Hz),
6.95-7.05 (2H, m) , 7.44-7.54 (1H, m) .
Reference Example 96 methyl 2-cyano-4-(4-cyclohexylphenyl)-4-oxobutanoate
4-Cyclohexylacetophenone (10.0 g) was dissolved in chloroform (30 mL) and diethyl ether (30 mL), and bromine io (8.70 g) was slowly added dropwise. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hr, diluted with water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 2-bromo-l-(5-cyclohexylpyridin-2yl)ethanone (15.8 g) as an oil. This was dissolved in tetrahydrofuran (20 mL), and added dropwise to a mixture of methyl cyanoacetate (4.95 g), diisopropylethylamine (16.2 g) and tetrahydrofuran (50 mL) . The reaction mixture was stirred at room temperature for 20 hr, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexaneethyl acetate=4:1_>3:1) to give the title compound as an oil (yield 12.1 g, 82%).
1H-NMR (CDC13)5: 1.20-1.51 (5H, m) , 1.70-1.90 (5H, m) , 2.512.64 (1H, m), 3.47-3.73 (1H, m) , 3.58-3.88 (1H, m), 3.85 (3H,
s), 4.09-4.19 (1H, m), 7.32 (2H, d, J=8.1 Hz), 7.89 (2H, d, J=8.1 Hz).
Reference Example 97 ethyl 2-chloro-5-(2,6-difluorophenyl)-lH-pyrrole-3-carboxylate A solution (14 mL) of ethyl 2-cyano-4-(2,635 difluorophenyl)-4-oxobutanoate (13.83 g) in ethyl acetate was ' 104
2015268744 15 Dec 2015 added dropwise to 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) at 10-15°C. The mixture was stirred at room temperature for 12 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1_>8: 2) to give the title compound as yellow crystals (yield 10.0 g, 68%). 1H-NMR (CDC13)6: 1-38 (3H, t, J=7.2 Hz), 4.34 (2H, q, J=7.2 Hz), 6.95-7.04 (2H, m) , 7.14-7.23 (2H, m), 9.20 (1H, br) . Reference Example 98 io methyl 2-chloro-5-(4-cyclohexylphenyl)-lH-pyrrole-3carboxylate 14% Hydrogen chloride - 1,4-dioxane solution (50 mL) was added to methyl 2-cyano-4-(4-cyclohexylphenyl)-4-oxobutanoate (12.1 g) and the mixture was stirred at room temperature for 8 hr and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether and collected by filtration to give a nearly
1:1 mixture (3.41 g) of the title compound and methyl 2-amino5-(4-cyclohexylphenyl)-3-furoate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexaneethyl acetate=7:2) to give the title compound as crystals (yield 0.64 g, 5%).
XH-NMR (CDC13)5: 1.22-1.48 (5H, m), 1.71-1.91 (5H, m) , 2.462.58 (1H, m), 3.86 (3H, s), 6.81 (1H, d, J=3.2 Hz), 7.23 (2H, d, J—θ.3 Hz), 7.36 (2H, d, J=8.3 Hz), 8.67 (1H, brs).
Reference Example 99 methyl 2-chloro-4-fluoro-5-phenyl-lH-pyrrole-3-carboxylate ' To a suspension of methyl 2-chloro-5-phenyl-lH-pyrrole-3 carboxylate (4.66 g) synthesized from methyl cyanoacetate and phenacyl bromide in the same manner as in Reference Example 95 and Reference Example 97 in acetonitrile (200 mL) was added
2,6-dichloro-N-fluoropyridinium triflate (6.26 g) over 10 min 105
2015268744 15 Dec 2015 under ice-cooling. The reaction mixture was stirred at the same temperature for 2 hr and at room temperature for 2 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:l-»7:3) to give the title compound as a pale-yellow solid (yield 815 io mg, 16%). More specifically, to a solution of methyl cyanoacetate (41 g) and diisopropylethylamine (117 g) in tetrahydrofuran (2600 mL) was added dropwise a solution of phenacyl bromide (75 g) in tetrahydrofuran (370 mL). The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give methyl 2-cyano-4-phenyl-4-oxobutanoate as a brown oil (yield 77.4 g, 95%). To a solution (125 mL) of ethyl 2-cyano-4-(2,6difluorophenyl)-4-oxobutanoate (25 g) in ethyl acetate was added dropwise 4 mol/L hydrogen chloride-ethyl acetate solution (25 mL) . The mixture was stirred at room temperature for 18 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give methyl 2-chloro-5-phenyl-lH-pyrrole-3-carboxylate as colorless crystals (yield 10.0 g, 37%). The title compound was synthesized from the thus-obtained methyl 2-chloro-5-phenyl35 lH-pyrrole-3-carboxylate.
106
2015268744 15 Dec 2015 1H-NMR (CDC13)5: 3.90 (3H, s) , 7.26-7.32 (1H, m) , 7.40-7.60 (4H, m), 8.29 (1H, br) .
Reference Example 100 ethyl 5-(2,6-difluorophenyl)-lH-pyrrole-3-carboxylate 5 To a solution of ethyl 2-chloro-5-(2,6-difluorophenyl)lH-pyrrole-3-carboxylate (9.82 g) in ethanol (200 mL) was added 10% palladium carbon (50% containing water, 4.91 g), and the mixture was stirred under a hydrogen atmosphere at 40°C for 72 hr. The reaction mixture was filtered, and the filtrate was io concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:l) to give the title compound as colorless crystals (yield 3.80 g, 24%).
XH-NMR (CDC13)5: 1-37 (3H, t, J=7.2 Hz), 4.32 (2H, q, J=7.2
Hz), 6.94-7.04 (2H, m), 7.11-7.21 (1H, m), 7.24-7.27 (1H, m) , 7.54-7.55 (1H, m), 9.37 (1H, br).
Reference Example 101 methyl 5-(4-cyclohexylphenyl)-lH-pyrrole-3-carboxylate
To a solution of a nearly 1:1 mixture (3.41 g) of methyl
2-chloro-5-(4-cyclohexylphenyl)-lH-pyrrole-3-carboxylate and methyl 2-amino-5-(4-cyclohexylphenyl)-3-furoate in methanol (30 mL) and ethyl acetate (10 mL) was added 10% palladium carbon (50% containing water, 0.34 g), and the mixture was stirred under a hydrogen atmosphere at 50°C for 14 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:l->2:1) to give the title compound as crystals (yield 1.25 g, 41%).
1H-NMR (CDC13)5: 1.19-1.50 (5H, m) , 1.73-1.93 (5H, m) , 2.43-
2.57 (1H, m), 3.84 (3H, s), 6.86 (1H, s), 7.24 (2H, d, J=8.3
Hz) , 7.41 (2H, d, J=8.3 Hz) , 7.45 (1H, dd, J=3. 0, 1.7 Hz),
8.73 (1H, brs) .
Reference Example 102
methyl 4-fluoro-5-phenyl-lH-pyrrole-3-carboxylate 107
2015268744 15 Dec 2015
Methyl 2-chloro-4-fluoro-5-phenyl-lH-pyrrole-3carboxylate (0.92 mg), 10% palladium carbon (50% containing water, 0.20 g) and triethylamine (0.56 mL) were suspended in methanol (30 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction mixture was filtered through celite, and the insoluble material was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1_»1:1) io to give the title compound as a colorless solid (yield 0.69 g, 87%) .
’’H-NMR (CDC13)5: 3.87 (3H, s) , 7.24-7.31 (2H, m) , 7.39-7.46 (2H, m), 7.51-7.54 (2H, m), 8.32 (1H, br).
Reference Example 103 [5-(2, 6-difluorophenyl)-lH-pyrrol-3-yl]methanol
A solution (35 mL) of ethyl 5-(2,6-difluorophenyl)-1Hpyrrole-3-carboxylate (3.35 g) in tetrahydrofuran was cooled to -50°C, and a 1.5 mol/L solution (30 mL) of diisobutylaluminum hydride in toluene was added dropwise by small portions. The mixture was stirred at the same temperature for 1 hr, water was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, celite and anhydrous magnesium sulfate were added and the mixture was further stirred for 15 min. The suspension was filtrated, and the obtained filtrate was concentrated under reduced pressure to give the title compound as pale-red crystals (yield 2.70 g, 97%) .
1H-NMR (CDC13)5: 1-46 (1H, br) , 4.64 (2H, s) , 6.88-7.02 (4H,
m), 7.06-7.16 (1H, m) , 9.07 (1H, br).
Reference Example 104 [5-(4-cyclohexylphenyl)-lH-pyrrol-3-yl]methanol
To a solution of methyl 5-(4-cyclohexylphenyl)-1Hpyrrole-3-carboxylate (3.0 g) in absolute tetrahydrofuran (40 mL) was added dropwise a 1.5 mol/L solution (21.0 mL) of 108
2015268744 15 Dec 2015 diisobutylaluminum hydride in toluene at -78°C. The mixture was further stirred at the same temperature for 2 hr. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl io acetate=l:l) to give the title compound as crystals (yield 1.07 g, 40%).
‘‘H-NMR (CDC13)5: 1.16-1.50 (5H, m) , 1.69-1.93 (5H, m) , 2.452.55 (1H, m), 4.60 (2H, s), 6.45-6.51 (1H, m) , 6.81-6.86 (1H, m), 7.21 (2H, d, J=8.3 Hz), 7.39 (2H, d, J=8.3 Hz), 8.30 (1H, br), 1H not detected.
Reference Example 105
5-(2,6-difluorophenyl)-lH-pyrrole-3-carbaldehyde
To a solution (26 mL) of [5-(2,6-difluorophenyl)-1Hpyrrol-3-yl]methanol (2.56 g) in acetonitrile were added tetra-n-propylammonium perruthenate (430 mg), Nmethylmorpholine N-oxide (2.15 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (60 mL) and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l:l) to give the title compound as pale-red crystals (yield 1.94 g, 77%) .
1H-NMR (CDC13)5: 6.97-7.06 (2H, m) , 7.16-7.24 (1H, m) , 7.2830 7.31 (1H, m) , 7.56-7.58 (1H, m), 9.55 (1H, br), 9.88 (1H, s) . Reference Example 106
5-(4-cyclohexylphenyl)-lH-pyrrole-3-carbaldehyde
To a solution (35 mL) of [5-(4-cyclohexylphenyl)-1Hpyrrol-3-yl]methanol (1.00 g) in acetonitrile were added tetra-n-propylammonium perruthenate (115 mg) , N109
2015268744 15 Dec 2015 methylmorpholine N-oxide (0.60 g) and molecular sieves 4A powder (1.15 g) under ice-cooling. The mixture was stirred at room temperature for 1.5 hr, and the reaction mixture was suspended in ethyl acetate, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:l) to give the title compound as crystals (yield 0.53 g, 53%).
1H-NMR (CDC13)5: 1.17-1.49 (5H, m) , 1.70-1.95 (5H, m) , 2.4510 2.58 (1H, m), 6.89 (1H, s), 7.25 (2H, d, J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz), 7.47 (1H, s), 8.99 (1H, brs), 9.82 (1H, s). Reference Example 107 lH-pyrrole-3-carbaldehyde
To a suspension of sodium hydride ¢13.7 g) in tetrahydrofuran (450 mL) was added dropwise pyrrole (17.4 g) under ice-cooling. The reaction mixture was stirred at the same temperature for 1.5 hr, and triisopropylsilyl chloride (50.0 g) was added dropwise at the same temperature. The mixture was further stirred at below 10°C for 1.5 hr, ice water was added and the mixture was extracted with diethyl ether.
The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution of the residue (57.7 g) in dichloromethane (30 mL) was added at once to a suspension of (chloromethylene)dimethylammonium chloride (36.5 g) in dichloromethane (500 mL) at 0°C. The reaction mixture was refluxed for 30 min and cooled to 0°C.
The resulting solid was collected by filtration, and washed with diethyl ether. The obtained solid was dissolved in water (50 mL), a 1 mol/L aqueous sodium hydroxide solution (500 mL) was added at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was extracted with chloroform and ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound as pale-brown crystals (yield 9.4 g, 38%).
110
2015268744 15 Dec 2015 ^-NMR (CDC13)5: 6.68-6.70 (1H, m), 6.83-6.86 (1H, m) , 7.457.47 (1H, m), 9.00-9.20 (1H, m) , 9.82 (1H, s) .
Reference Example 108
2-chloro-2,2-difluoro-l-(2-methylphenyl)ethanone
Magnesium (flake, 6.2 g) was suspended in diethyl ether (10 mL), and iodine (small amount) was added and a solution of 2-bromotoluene (43.26 g) in diethyl ether (100 mL) were slowly added dropwise. After stirring at room temperature for 1 hr, the reaction mixture was added dropwise to a solution of io chlorodifluoroacetic acid (10.0 g) in diethyl ether (100 mL) at -10°C, and the mixture was stirred at 0°C for 1 hr.
Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
The residue was distilled under reduced pressure (boiling point: 81-82°C/12-13 mmHg) to give the title compound as a pale-yellow oil (yield 4.9 g, 31%) .
1H-NMR (CDC13)6: 2.54 (3H, s) , 7.29-7.36 (2H, m) , 7.47-7.53 (1H, m) , 7.89-7.92 (1H, m).
Reference Example 109
2,2-difluoro-2-iodo-l-(2-methylphenyl)ethanone
To a suspension of zinc (1.6 g) in acetonitrile (40 mL) were added trimethylsilyl chloride (3.1 mL) and 2-chloro-2,225 difluoro-1-(2-methylphenyl)ethanone (4.0 g), and the mixture was stirred at 55°C for 3 hr. The reaction mixture was allowed to cool to room temperature, iodine (3.5 g) was added, and the mixture was further stirred for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen sulfite solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane) to give the title compound as a yellow oil (yield 2.6 g, 46%).
111
2015268744 15 Dec 2015 ’’H-NMR (CDC13)5: 2.51 (3H, s) , 7.26-7.35 (2H, m) , 7.46-7.51 (1H, m), 7.91-7.94 (1H, m) .
Reference Example 110
2, 2-difluoro-4-iodo-l- (2-methylphenyl)-4-trimethylsilylbutan5 1-one
Under a nitrogen atmosphere, to a mixture of tetrakis(triphenylphosphine)palladium (0.52 g) and vinyltrimethylsilane (1.9 mL) was added 2,2-difluoro-2-iodo-l(2-methylphenyl)ethanone (2.6 g), and the mixture was stirred io at room temperature for 2 hr. Diethyl ether was added to the reaction mixture, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane) to give the title compound as a colorless oil (yield 2.6 g, 74%).
(CDC13)5: 0-21 (9H, s), 2.50 (3H, s) , 2.70-2.89 (2H, m) , 3.19-3.24 (1H, m) , 7.27-7.32 (2H, m), 7.42-7.48 (1H, m), 7.897.92 (1H, m).
Reference Example 111 20 3-fluoro-2- (2-methylphenyl)-lH-pyrrole
To a solution (20 mL) of 2,2-difluoro-4-iodo-l-(2methylphenyl)-4-trimethylsilylbutan-l-one (2.5 g) in tetrahydrofuran was added 28% aqueous ammonia solution (6 mL), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was dissolved in acetonitrile (15 mL) and water (8 mL), and potassium fluoride (0.75 g) was added. The reaction mixture was stirred at 60°C for 3 hr, and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica· gel 112
2015268744 15 Dec 2015 column chromatography (eluent: hexane-ethyl acetate=20:1) to give the title compound as a pale-yellow oil (yield 0.87 g,
78%) .
(CDC13)5: 2.39 (3H, d, J=1.5Hz), 6.06-6.08 (1H, m) ,
6.60-6.63 (1H, m), 7.19-7.33 (4H, m) , 7.71 (1H, brs).
Reference Example 112 5-bromo-lH-pyrrole-3-carbaldehyde
A solution of lH-pyrrole-3-carbaldehyde (19.1 g) in tetrahydro furan (300 mL) was cooled to -70°C, and a solution of io N-bromosuccinimide (35.8 g) in N,N-dimethylformamide (100 mL) was added dropwise. After stirring at the same temperature for 1 hr, the mixture was raised to -10°C over 2 hr and further stirred for 30 min. Ice water was added to the reaction mixture at 0°C, and the mixture was allowed to warm to room temperature and extracted with ethyl acetate. The extract was washed with 10% aqueous citric acid solution, 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crystals obtained as a residue were washed with diisopropyl ether to give the title compound as colorless crystals (yield 17.7 g, 51%).
1H-NMR (CDC13)6: 6.65-6.66 (1H, m) , 7.37-7.38 (1H, m) , 8.80 (1H, br), 9.70 (1H, s).
Reference Example 113
5-(2-methylphenyl)-lH-pyrrole-3-carbaldehyde
5-Bromo-lH-pyrrole-3-carbaldehyde (100 mg), 2methylphenylboronic acid (94 mg) and sodium carbonate (146 mg) were suspended in a mixed solvent of 1,2-dimethoxyethane (5 mL) and water (2 mL), and the mixture was sufficiently degassed under a nitrogen atmosphere.
Tetrakis(triphenylphosphine)palladium (33 mg) was added, and the mixture was further degassed and refluxed at 105°C for 24 hr. The reaction mixture was allowed to cool to room temperature, and the mixture was extracted with water and ethyl acetate. The extract was washed with saturated brine,
113
2015268744 15 Dec 2015 dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1—>3:1) to give the title compound as colorless crystals (yield 72 mg,
68%).
•’•H-NMR (CDC13)6: 2.44 (3H, s) , 6.75-6.77 (1H, m) , 7.23-7.36 (4H, m), 7.50-7.51 (1H, m), 8.75 (1H, br), 9.85 (1H, s). Reference Example 114
4-chloro-5- (2-fluorophenyl)-lH-pyrrole-3-carbaldehyde io To a solution (15 mL) of 5-(2-fluorophenyl)-lH-pyrrole-3carbaldehyde (1.0 g) in Ν,Ν-dimethylformamide was added Nchlorosuccinimide (0.71 g) at 0°C, and the mixture was stirred at 60°C for 2 hr. The mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1—>3:1) to give the title compound as a yellow powder (yield 0.55 g,
46%) .
1H-NMR (CDC13)5: 7.15-7.40 (3H, m) , 7.52 (1H, d, J=3.6 Hz), 7.97-8.03 (1H, m) , 9.24 (1H, br), 9.96 (1H, s) .
Reference Example 115
4-fluoro-5-(2-fluorophenyl)-lH-pyrrole-3-carbaldehyde
To a solution (60 mL) of 5-(2-fluorophenyl)-lH-pyrrole-3carbaldehyde (3.1 g) in tetrahydrofuran was added 2,6dichloro-N-fluoropyridinium triflate (5.6 g) at 0°C, and the mixture was stirred at the same temperature for 2 hr.
Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:l) to
114
2015268744 15 Dec 2015 give the title compound as white crystals (yield 0.43 g, 13%) . 1H-NMR (CDC13)5: 7.11-7.30 (4H, m) , 7.80-7.87 (1H, m) , 9.14 (1H, brs), 9.88 (1H, s).
Reference Example 116
4-fluoro-5-(2-methylphenyl)-lH-pyrrole-3-carbaldehyde
Sodium hydride (0.40 g) was washed twice with hexane and suspended in tetrahydrofuran (10 mL). A solution of 3-fluoro2-(2-methylphenyl)-IH-pyrrole (0.86 g) in tetrahydrofuran (3 mL) was added at 0°C, and the mixture was stirred at the same io temperature for 30 min. A solution (2 mL) of triisopropylsilyl trifluoroacetate (2.7 mL) in tetrahydrofuran was added at 0°C, and the mixture was stirred at the same temperature for 15 min. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL) and acetonitrile (2 mL), (chloromethylene)dimethylammonium chloride (1.6 g) was added, and the mixture was heated under reflux for 2 hr, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL), 1 mol/L aqueous sodium hydroxide solution (20 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:l) to give the title compound as a yellow oil (yield 0.48 g, 48%).
XH-NMR (CDC13)5: 2.38 (3H, s) , 7.23-7.32 (5H, m) , 8.38 (1H, brs), 9.87 (1H, s).
Reference Example 117
5-nitro-3-(trifluoromethyl)pyridin-2-ol
115
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2-Hydroxy-3-(trifluoromethyl)pyridine (3.0 g) was added to cone, sulfuric acid (18 mL) under ice-cooling, and the mixture was stirred at the same temperature for 5 min. Fuming nitric acid (90-95%, 7 mL) was added dropwise over 5 min, and the mixture was allowed to return to room temperature over 2 hr, heated to 50°C and stirred for 3 hr. After cooling to room temperature, the reaction mixture was poured into ice (200 g), • and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous io magnesium sulfate, and concentrated under reduced pressure.
The precipitate was washed with diisopropyl ether to give the title compound as a solid (yield 2.7 g, 69%).
’’’H-NMR (CDC13)6: 8.65-8.67 (1H, m) , 8.80-8.81 (1H, m) , 1H not detected.
Reference Example 118
2-chloro-5-nitro-3-(tri fluoromethyl) pyridine
A mixture of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.65 g), phosphorus pentachloride (3.17 g) and phosphorus oxychloride (1.5 mL) was stirred at 90°C for 3 hr. After cooling to room temperature, the reaction mixture was poured into ice, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1—»3:1) to give the title compound as a yellow oil (yield 2.21 g, 77%).
’’H-NMR (CDC13)6: 8.79-8.81 (1H, m) , 9.40-9.41 (1H, m) .
Reference Example 119
6-chloro-5-(trifluoromethyl)pyridine-3-amine
Reduced iron (1.3 g) and ammonium chloride (2.1 g) were added to water (40 mL), and the mixture was stirred at room temperature for 5 min. A solution of 2-chloro-5-nitro-3(trifluoromethyl)pyridine (1.8 g) in methanol (40 mL) was added, and the mixture was stirred at room temperature for 1 hr. Reduced iron (2.3 g) was added, and the mixture was
116
2015268744 15 Dec 2015 further stirred at the same temperature for 3 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1_»1:1) to give the title compound as a solid (yield 1.0 g, 65%).
XH-NMR (CDC13)6: 7.29 (1H, m), 7.99 (1H, m) , 2H not detected.
io Reference Example 120
6-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride
Under ice-cooling, thionyl chloride (4 mL) was added dropwise over 20 min to water (27 mL) . The mixture was stirred at room temperature for 12 hr to give a sulfur dioxide15 containing solution. Separately, 6-chloro-5(trifluoromethyl)pyridine-3-amine (1.14 g) was added to concentrated hydrochloric acid (9 mL) with stirring under icecooling, and concentrated hydrochloric acid (9 mL) was further added. A solution of sodium nitrite (0.44 g) in water (6 mL) was added dropwise over 10 min. The reaction mixture was gradually added at 5°C to the above-mentioned sulfur dioxidecontaining solution added with cuprous chloride (15 mg). Under ice-cooling, the mixture was further stirred for 30 min, and the precipitate was collected by filtration and washed with water. The obtained precipitate was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:l->9:1) to give the title compound as an orange solid (yield 437 mg, 27%) .
XH-NMR (CDC13)5: 8-58 (1H, m) , 9.18 (1H, m) .
Reference Example 121
6-chloro-2-methylpyridine-3-sulfonyl chloride
Under ice-cooling, thionyl chloride (4 mL) was added dropwise to water (24 mL) over 20 min. The mixture was stirred at room temperature for 12 hr to give a sulfur dioxide55 containing solution. Separately, to the concentrated 117
2015268744 15 Dec 2015 hydrochloric acid (6 mL) was added 5-amino-2-chloro-6methylpyridine (1.0 g) with stirring under ice-cooling, and a solution of sodium nitrite (0.5 g) in water (2 mL) was added dropwise over 10 min. The reaction mixture was gradually added at 5°C to the above-mentioned sulfur dioxide-containing solution added with cuprous chloride (10 mg). Under icecooling, the mixture was further stirred for 30 min, and the precipitate was collected by filtration, and washed with water to give the title compound as a pale-yellow solid (yield 1.1 io g, 67%) .
1H-NMR (CDC13)5: 2.99 (3H, s) , 7.41 (1H, dd, J=8.7, 0.9 Hz),
8.26 (1H, d, J=8.4 Hz) .
Reference Example 122 ethyl 1-[(5-bromopyridin-3-yl) sulfonyl]-5-phenyl-lH-pyrrole-315 carboxylate
By a similar reaction as in Reference Example 40 and using 5-bromo-6-chloropyridine-3-sulfonyl chloride (3.49 g), the title compound was obtained as a yellow solid (yield 1.63 g, 38%) .
XH-NMR (CDC13)5: 1.35-1.39 (3H, m) , 4.29-4.37 (2H, m) , 6.60 (1H, s), 7.18-7.20 (2H, m), 7.35-7.51 (4H, m), 8.06 (1H, s), 8.45 (1H, s), 8.78 (1H, s) .
Reference Example 123 ethyl 5-phenyl-l-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl}25 lH-pyrrole-3-carboxylate
By a similar reaction as in Reference Example 40 and using 6-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride (413 mg), the title compound was obtained as a colorless solid (yield 191 mg, 35%).
so XH-NMR (CDCl3)fi: 1.37 (3H, t, J=7.2 Hz), 4.33 (2H, dd, J=14.4,
7.2 Hz), 6.61 (1H, s), 7.16-7.18 (2H, m), 7.33-7.45 (3H, m), 7.65 (1H, s), 8.09 (1H, s), 8.75 (1H, s), 8.98 (1H, s). Reference Example 124 ethyl 1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-lH-pyrrole35 3-carboxylate
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By a similar reaction as in Reference Example 40 and using 6-chloro-2-methylpyridine-3-sulfonyl chloride (543 mg), the title compound was obtained as a red oil (yield 135 mg,
18%) .
1H-NMR (CDC13)5: 1.35-1.40 (3H, m) , 2.47 (3H, s) , 4.33 (2H, dd, J=14.1, 6.9 Hz), 6.59 (1H, d, J=1.8 Hz), 6.82-7.49 (7H, m), 8.21 (1H, d, J=2.1 Hz), 8.51 (1H, dd, J=4.8, 1.8 Hz).
Reference Example 125 methyl 4-fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole10 3-carboxylate
By a similar reaction as in Reference Example 36 and using methyl 4-fluoro-5-phenyl-lH-pyrrole-3-carboxylate (172 mg), the title compound was obtained as a colorless solid (yield 206 mg, 73%) . More specifically, to a solution of methyl 4-fluoro-5-phenyl-lH-pyrrole-3-carboxylate (172 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 94 mg), and the mixture was stirred for 15 min. 15-Crown-5 (0.48 mL) was added, and the mixture was further stirred for 15 min. Pyridine-3-sulfonyl chloride hydrochloride (219 mg) was added and the mixture was stirred for 30 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1—>1:1) to give the title compound as a colorless solid (yield 206 mg, 73%) .
1H-NMR (CDC13)5: 3.89 (3H, s) , 7.17-7.20 (2H, m) , 7.26-7.55 (5H, m), 7.95 (1H, d, J=4.8 Hz), 8.50-8.51 (1H, m), 8.76-8.78 (1H, m) .
Reference Example 126
1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-lH-pyrrole-3carbaldehyde
By a similar reaction as in Reference Example 62 and
-using ethyl 1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-lH119
2015268744 15 Dec 2015 pyrrole-3-carboxylate (1.63 g) , the title compound was obtained as a pale-yellow solid (yield 1.18 g, 80%).
XH-NMR (CDC13)6: 6.63 (1H, s), 7.17-7.20 (2H, m) , 7.36-7.39 (2H, m), 7.50-7.52 (2H, m), 8.10 (1H, s) , 8.46 (1H, s), 8.795 8.80 (1H, m), 9.91 (1H, s).
Reference Example 127
5-phenyl-l-{[5-(trifluoromethyl)pyridin-3-yl]sulfonylJ-1Hpyrrole-3-carbaldehyde
By a similar reaction as in Reference Example 62 and io using ethyl 5-phenyl-l-{[(5-trifluoromethyl)pyridin-3yl]sulfonyl}-lH-pyrrole-3-carboxylate (190 mg), the title compound was obtained as a colorless solid (yield 138 mg,
83%) .
XH-NMR (CDC13)5: 6.64 (1H, d, J=1.5 Hz), 7.15-7.18 (2H, m) ,
7.33-7.38 (2H, m) , 7.44-7.47 (1H, m), 7.63-7.64 (1H, m), 8.14 (1H, d, J=1.5 Hz), 8.76 (1H, d, J=2.1 Hz), 9.00 (1H, d, J=1.5 Hz) , 9.92 (1H, s) .
Reference Example 128
1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-lH-pyrrole-320 carbaldehyde
By a similar reaction as in Reference Example 62 and using ethyl 1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-lHpyrrole-3-carboxylate (364 mg), the title compound was obtained as an orange solid (yield 182 mg, 57%).
1H-NMR (CDC13)5: 2.47 (3H, s) , 6.62 (1H, d, J=1.8 Hz), 6.836.90 (1H, m), 7.02-7.04 (2H, m) , 7.16-7.31 (3H, m), 7.39-7.42 (1H, m), 8.24 (1H, s) , 8.52-8.54 (1H, m), 9.93 (1H, s) . Reference Example 129
4-fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-330 carbaldehyde
Under a nitrogen atmosphere, a solution of methyl 4fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carboxylate (200 mg) in tetrahydrofuran (10 mL) was cooled to -78°C, and a 1.5 mol/L solution (1.85 mL) of diisobutylaluminum hydride in toluene was added with stirring. After stirring at
120
2015268744 15 Dec 2015 the same temperature for 15 min, the mixture was' raised to 0°C over 1.5 hr. Water (20 mL) was added, and the mixture was stirred at the same temperature for 5 min. After stirring, ethyl acetate (20 mL) was added, and the mixture was stirred for 15 min, and then stirred at room temperature for 20 min.
The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and - concentrated under io reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), manganese dioxide (75% chemically treated product,
1.0 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-»1:2) to give the title compound as a colorless solid (yield 123 mg, 67%).
H-NMR (CDC13)5·. 7.17-7.20 (2H, m) , 7.26-7.57 (5H, m) , 7.96 (1H, d, J=4.8 Hz), 8.50-8.51 (1H, m) , 8.76-8.80 (1H, m) , 9.92 (1H, S).
Reference Example 130
5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carbaldehyde
To a solution of 5-(2,6-difluorophenyl)-lH-pyrrole-3carbaldehyde (420 mg) in tetrahydrofuran (42 mL) was added sodium hydride (60% in oil, 244 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (1.34 g) was added dropwise and the mixture was stirred for 30 min. 330 Pyridylsulfonyl chloride hydrochloride (565 mg) was added, and the mixture was further stirred for 1 hr. The reaction mixture was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue 121
2015268744 15 Dec 2015 was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7 :3->l: 1), and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 590 mg, 84%) .
5 1H-NMR (CDC13)5: 6.76 (1H, d, J=1.9 Hz), 6.90-6.95 (2H, m),
7.40-7.52 (2H, m), 7.77-7.81 (1H, m) , 8.18 (1H, d, J=1.9 Hz),
8.65-8.66 (1H, m), 8.85-8.87 (1H, m), 9.91 (1H, s) •
Reference Example 131
5-(4-cyclohexylphenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrole-310 carbaldehyde
Sodium hydride (60% in oil, 68 mg) was added to a solution of 5-(4-cyclohexylphenyl)-lH-pyrrole-3-carbaldehyde (0.17 g) in tetrahydrofuran (12 mL) at room temperature. The mixture was stirred for 20 min, 3-pyridinesulfonyl chloride (0.19 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2-»2:1) to give the title compound as crystals (yield 0.26 g, 97%).
1H-NMR (CDC13)6: 1.21-1.53 (5H, m) , 1.73-1.98 (5H, m) , 2.502.60 (1H, m), 6.57 (1H, d, J=1.9Hz), 7.03-7.09 (2H, m), 7.1325 7.29 (3H, m), 7.48 (1H, ddd, J=8.3, 2.0, 1.9 Hz), 8.11 (1H, d, J=1.9 Hz), 8.49 (1H, d, J=2.3 Hz), 8.73 (1H, dd, J=4.8, 1.6 Hz), 9.89 (1H, s).
Reference Example 132
1-[(6-chloropyridin-3-yl)sulfonyl]-5-(2-fluorophenyl)-1H30 pyrrole-3-carbaldehyde
By a similar reaction as in Reference Example 65 and using 5-(2-fluorophenyl)-lH-pyrrole-3-carbaldehyde (893 mg) and.6-chloropyridine-3-sulfonyl chloride (1.30 g), the title compound was obtained as a pale-red solid (yield 1.14 g, 66%) .
More specifically, 5-(2-fluorophenyl)-ΙΗ-pyrrole-3122
2015268744 15 Dec 2015 carbaldehyde (893 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 226 mg) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (1.1 mL) was added and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridine-3-sulfonyl chloride (1.30 g) was added. The reaction mixture was stirred at room temperature for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous io magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:l—>3:2) to give the title compound as a pale-red solid (yield 1.14 g, 66%).
XH-NMR (CDC13)6: β·71 (1H, d, J=9.0 Hz), 7.05 (1H, t, J=9.0
Hz), 7.19-7.23 (2H, m), 7.38 (1H, d, J=8.4 Hz), 7.45-7.53 (1H, m), 7.63-7.67 (1H, m), 8.11 (1H, d, J=1.8 Hz), 8.33 (1H, d, J=2.7 Hz) , 9.91 (1H, s).
Reference Example 133
5-(2-fluorophenyl)-1-[ (6-methylpyridin-3-yl)sulfonyl]-1H20 pyrrole-3-carbaldehyde
Under an argon atmosphere, a mixture of 1—[(6— chloropyridin-3-yl)sulfonyl]-5-(2-fluorophenyl)-lH-pyrrole-3carbaldehyde (365 mg), methylboronic acid (90 mg), tetrakis(triphenylphosphine)palladium (116 mg), potassium carbonate (691 mg) and 1,4-dioxane (25 mL) was stirred at 80°C for 3 days. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1->1:1) to give the title compound as a yellow solid (yield 134 mg, 39%).
hi-NMR (CDC13)5: 2.64 (3H, s) , 6.67 (1H, d, J=1.8 Hz), 7.04 (1H, t, J=8.4 Hz), 7.17-7.21 (3H, m) , 7.45-7.50 (1H, m), 7.58
123
2015268744 15 Dec 2015 (1H, dd, J=8.7, 3.6Hz), 8.12 (1H, d, J=1.8 Hz), 8.45 (1H, d, J=2.4 Hz), 9.89 (1H, s).
Reference Example 134
5-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-lH-pyrrole-35 carbaldehyde
By a similar reaction as in Reference Example 65 and using 5-(2-fluorophenyl)-lH-pyrrole-3-carbaldehyde (190 mg) and pyridine-2-sulfonyl chloride (231 mg), the title compound was obtained as a pale-red solid (yield 183 mg, 55%).
io 1H-NMR (CDC13)5: 5.67 (1H, d, J=1.8 Hz), 6.97 (1H, t, J=8.7 Hz), 7.07-7.10 (2H, m) , 7.36-7.42 (1H, m) , 7.52-7.55 (2H, m), 7.76-7.82 (1H, m), 8.23 (1H, d, J=1.5 Hz), 8.67 (1H, d, J=4.5 Hz), 9.92 (1H, s). ·
Reference Example 135
5-(2-fluorophenyl)-1-[(l-methyl-lH-pyrazol-4-yl)sulfonyl]-1Hpyrrole-3-carbaldehyde
By a similar operation as in Reference Example 65 and using 5-(2-fluorophenyl)-lH-pyrrole-3-carbaldehyde (189 mg) and l-methyl-lH-pyrazole-4-sulfonyl chloride (217 mg), the title compound was obtained as yellow crystals (yield 217 mg, 65%) .
1H-NMR (CDC13)§: 3.85 (3H, s) , 6.67 (1H, d, J=1.8 Hz), 7.047.11 (1H, m), 7.17-7.22 (1H, m), 7.25-7.35 (3H, m), 7.43-7.50 (1H, m), 8.06 (1H, d, J=1.5 Hz), 9.86 (1H, s).
Reference Example 136
5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carbaldehyde
To a solution of 5-(2-methylphenyl)-lH-pyrrole-3carbaldehyde (371 mg) in tetrahydrofuran (10 mL) were added sodium hydride (60% in oil, 288 mg) and 15-crown-5 (1.32 g) at room temperature. After stirring for 5 min, a suspension of pyridine-3-sulfonyl chloride hydrochloride (642 mg) in N,Ndimethylformamide (5 mL) was added at the same temperature. After stirring for 15 min, ice water was added, and the mixture was extracted with ethyl acetate. The extract was 124
2015268744 15 Dec 2015 washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6: l->3:1) to give the title compound as a red oil (yield 521 mg, 80%).
“H-NMR (CDC13)5: 1.θ2 (3H, s) , 6.56 (1H, d, J=1.5Hz), 6.876.90 (1H, m), 7.11-7.19 (2H, m), 7.30-7.39 (2H, m), 7.56-7.60 (1H, m), 8.15 (1H, d, J=1.5 Hz), 8.52-8.53 (1H, m) , 8.80-8.82 (1H, m), 9.92 (1H, s).
io Reference Example 137
4-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrο1e-3-carbaldehyde
A suspension of sodium hydride (60% in oil, 216 mg) in tetrahydro furan (5 mL) was cooled to 0°C, a solution of 415 chloro-5-(2-fluorophenyl)-lH-pyrrole-3-carbaldehyde (335 mg) in tetrahydrofuran (5 mL), 15-crown-5 (991 mg), and pyridine3- sulfonyl chloride hydrochloride (482 mg) were added at 10°C or below. After stirring for 15 min, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4 : l->2:1) to give the title compound as a yellow powder (yield 429 mg, 78%) .
'“'H-NMR (CDCl3)5: 7.02-7.08 (1H, m) , 7.19-7.29 (2H, m) , 7.377.41 (1H, m), 7.50-7.57 (1H, m), 7.68-7.72 (1H, m), 8.15 (1H, s), 8.54-8.55 (1H, m), 8.83-8.86 (1H, m), 9.97 (1H, s). Reference Example 138
4- fluoro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H30 pyrrole-3-carbaldehyde
Sodium hydride (60% in oil, 0.25 g) was washed twice with hexane and suspended in tetrahydrofuran (10 mL) . A solution (5 mL).of 4-fluoro-5-(2-fluorophenyl)-lH-pyrrole-3-carbaldehyde (0.43 g) in tetrahydro fur an was added at 0°C, and the mixture was stirred at the same temperature for 30 min. 15-Crown-5 125
2015268744 15 Dec 2015 (1.3 mL) and 3-pyridinesulfonyl chloride hydrochloride (0.68 g) were added at 0°C, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l:l) to give the title compound io as pale-yellow crystals (yield 0.55 g, 76%).
’’H-NMR (CDC13)5: 7.02-7.08 (1H, m) , 7.20-7.31 (2H, m) , 7.367.41 (1H, m), 7.48-7.55 (1H, m), 7.67-7.71 (1H, m), 8.00 (1H, d, J=5.1 Hz), 8.55-8.56 (1H, m), 8.83-8.85 (1H, m) , 9.93 (1H, s) .
Reference Example 139
4-fluoro-5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrole-3-carbaldehyde
Sodium hydride (60% in oil, 0.11 g) was washed twice with hexane and suspended in tetrahydrofuran (10 mL). A solution (5 mL) of 4-fluoro-5-(2-methylphenyl)-lH-pyrrole-3-carbaldehyde (0.45 g) in tetrahydrofuran was added at 0°C, and the mixture was stirred at the same temperature for 15 min. A solution (2 mL) of 15-crown-5 (0.56 mL) and 3-pyridinesulfonyl chloride (0.44 g) in tetrahydrofuran was added at 0°C, and the mixture was stirred at the same temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l:1) to give the title compound as pale-yellow crystals (yield 0.59 g, 77%) .
1H-NMR (CDC13)5: 1.77 (3H, s) , 7.02-7.04 (1H, m) , 7.17-7.23 (2H, m), 7.29-7.34 (1H, m) , 7.37-7.42 (1H, m), 7.54-7.58 (1H,
126
2015268744 15 Dec 2015
m), 8.00 (1H, d, 0=4.5 Hz), 8.49-8.50 (1H, m), 8.81-8.83 (1H, m) , 9.92 (1H, s) .
Reference Example 140
2-chloro-5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H5 pyrrole-3-carbaldehyde
To a solution of 5-(2,6-difluorophenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrole-3-carbaldehyde (250 mg) in tetrahydrofuran (10 mL) and Ν,Ν-dimethylformamide (10 mL) was added N-chlorosuccinimide (1.06 g) and the mixture was stirred io for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed.with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is was purified by silica gel column chromatography (eluent:
hexane-ethyl acetate=7 :3_>1:1) to give the title compound as a pale-yellow oil (yield 160 mg, 58%) .
1H-NMR (CDC13)5: 6.74 (1H, s) , 7.00-7.05 (2H, m) , 7.42-7.56 (2H, m), 8.10-8.14 (1H, m), 8.91 (1H, dd, J=4.9, 1.5 Hz), 9.07 (1H, d, J=2.1 Hz), 9.92 (1H, s) .
Reference Example 141
2-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrole-3-carbaldehyde
To a solution of 5-(2-fluorophenyl)-1-(pyridin-325 ylsulfonyl)-lH-pyrrole-3-carbaldehyde (331 mg) in Ν,Νdimethylformamide (33 mL) was added N-chlorosuccinimide (268 mg) and the mixture was stirred at 60°C for 1 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3->l: 1) to give the title compound as a colorless oil (yield 250 mg,
68%) .
127
2015268744 19 Feb 2016
Ai-NMR (CDC13)5: 6.65 (1H, s) , 7.13-7.35 (3H, m) , 7.45-7.55 (2H, m), 8.09-8.13 (1H, m) , 8.90-9.03 (2H, m), 9.92 (1H, s) . Reference Example 142 tert-butyl ({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl5 lH-pyrrol-3-yl}methyl)methylcarbamate
1-[(5-Bromopyridin-3-yl)sulfonyl]-5-phenyl-lH-pyrrole-3carbaldehyde (1.18 g) was dissolved in absolute tetrahydrofuran (15 mL), a 2 mol/L solution (4.6 mL) of methylamine in tetrahvdrofuran was added, and the mixture was io stirred at room temperature for 16 hr. The reaction mixture was added to a solution of sodium borohydride (341 mg) in methanol (6 mL), and the mixture was stirred at the same temperature for 5 min. di-tert-Butyl bicarbonate (3.87 g) was added, and water (15 mL) and sodium hydrogencarbonate (1.26 g) were added 5 min later. The mixture was further stirred at room temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate-19:1->1:1), and fractions showing Rf values of 0.63, 0.30 and 0.075 (eluent: hexane-ethyl acetate=3:l) by TLC analysis were collected and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), manganese dioxide (75% chemically treated product, 3.0 g) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1_»1:1) to give the title compound as a colorless oil (yield 733 mg, 48%). 1H-NMR (CDC13)5: 1.47 (9H, s) , 2.82 (3H, s), 4.23 (2H, m) , 6.16 (1H, s), 7.21-7.56 (7H, m), 8.44 (1H, s), 8.76 (1H, s).
Reference Example 143
128
2015268744 19 Feb 2016 tert-butyl {[5-(2,4-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)IH-pyrrol-3-yl]methyl}me thyl carbamat e,
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-IH-pyrrols 3-yl]methylJmethylcarbamate (300 mg) , (2,4-dimethylphenyl)boronic acid (209 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 177 mg,.56%).
1H-NMR (CDC13)§: 1.46 (9H, s) , 1.89 (3H, s) , 2.36 (3H, s) , 2.83 ίο (3H, s), 4.25 (2H, brs), 6.03-6.04 (1H, m), 6.76 (1H, d, J=8.1
Hz), 6.92-6.95 (1H, m), 7.00 (1H, brs), 7.26-7.33 (2H, m), 7.61-7.65 (1H, m), 8.56-8.57 (1H, m) , 8.75-8.77 (1H, m). Reference Example 144 tert-butyl {[5-(2-formylphenyl)-1-(pyridin-3-ylsulfonyl)-1H25 pyrrol-3-yl]methyl}methylcarbamate tert-Butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-IH-pyrrol3-yl]methyl}methylcarbamate (430 mg) was dissolved in toluene (10 mL), and the mixture was sufficiently degassed.
Dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (66 mg) and tris(dibenzylideneacetone)dipalladium (0) (37 mg) were added at room temperature. The mixture was stirred for 30 min with degassing, and a 2 mol/L aqueous sodium carbonate solution (1.2 mL) and (2-formylphenyl)boronic acid (180 mg) were added. After further stirring at room temperature for 15 min, the mixture was heated to 120°C over 1 hr, and further stirred for 16 hr. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1_»1:1) to give the title compound as a yellow oil (yield 218 mg,
48%),.
1H-NMR (CDC13)5: 1.47 (9H, s) , 2.86 (3H, s) , 4.27 (2H, brs),
6.23 (1H, brs), 7.09-7.11 (1H, m) , 7.28-7.33 (1H, m), 7.43
129
2015268744 15 Dec 2015 (1H, d, J=1.2 Hz), 7.53-7.61 (3H, m) , 7.96-7.99 (1H, m), 8.498.50 (1H, in), 8.75-8.77 (1H, m) , 9.61-9.62 (1H, m) .
Reference Example 145 tert-butyl methyl{[5-[4-(methylsulfonyl)phenyl]-1-(pyridin-35 ylsulfonyl)-lH-pyrrol-3-yl]methyl}carbamate
A mixture of tert-butyl {[5-bromo-l- (p'yridin-3ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate (430 mg), 4(methanesulfonyl)phenylboronic acid (300 mg), tetrakis(triphenylphosphine)palladium (115 mg), sodium io carbonate (320 mg), 1,2-dimethoxyethane (10 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80°C for 14 hr. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1-»1:2) to give the title compound as an oil (yield 275 mg, 64%).
XH-NMR (CD‘C13)5: 1-26 (9H, s), 2:79 (3H, s) , 3.13 (3H, s) , 4.22 (2H, s), 6.26 (1H, s), 7.26-7.37 (2H, m), 7.44-7.71 (3H, m) ,
7.93 (2H, d, J=8.3 Hz), 8.58 (1H, d, J=2.1 Hz), 8.76 (1H, dd, J=4.9, 1.5 Hz).
Reference Example 146 tert-butyl ({5-[2-(hydroxymethyl)phenyl]-1-(pyridin-325 ylsulfonyl)-lH-pyrrol-3-yl}methyl)methylcarbamate tert-Butyl {[5-(2-formylphenyl)-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl]methyl}methylcarbamate (218 mg) was dissolved in tetrahydrofuran (2 mL), and sodium borohydride (24 mg) and methanol (1 mL) were added at 0°C. After stirring at the same temperature for 30 min, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l: 1->1:3) to give the title compound as a colorless oil 130
2015268744 15 Dec 2015 (yield 132 mg, 60%).
XH-NMR (CDC13)5: 1.46 (9H, s), 2.10-2.15 (1H, m), 2.85 (3H, s), 4.25 (2H, brs), 4.30-4.38 (2H, m), 6.12 (1H, d, J=1.5 Hz), 6.69-6.72 (1H, m), 7.13-7.18 (1H, m), 7.30-7.35 (2H, m), 7.445 7.49 (1H, m), 7.59-7.62 (2H, m), 8.50 (1H, d, J=2.4 Hz), 8.768.78 (1H, m).
Reference Example 147 5-me sityl-ΙΗ-ρyrrole-3-carbaldehyde
A mixture of 5-bromo-lH-pyrrole-3-carbaldehyde (0.87 g), io 2,4,6-trimethylphenylboronic acid (3.28 g), cesium carbonate (13.0 g), tri-tert-butylphosphine (0.10 g), tris(dibenzylideneacetone)dipalladium (0) (0.23 g) and mesitylene (200 mL) was stirred with heating under reflux for 5 hr. Water was added to the reaction mixture, and the mixture is was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:l) to give the title compound as a brown amorphous form (yield 0.30 g, 28%).
XH-NMR (CDC13)6: 2.11 (6H, s) , 2.32 (3H, s) , 6.51-6.52 (1H, m) , 6.93 (2H, s), 7.47-7.49 (1H, m), 9.82 (1H, s) , 1H not detected.
Reference Example 148
5-[2-(methylthio)phenyl]-lH-pyrrole-3-carbaldehyde
5-Bromo-lH-pyrrole-3-carbaldehyde (174 mg), [2(methylthio)phenyl]boronic acid (202 mg) and sodium carbonate (254 mg) were suspended in a mixed solvent of 1,2dimethoxyethane (5 mL) and water (2 mL), and the mixture was sufficiently degassed under a nitrogen atmosphere.
Tetrakis(triphenylphosphine)palladium (58 mg) was added, and the mixture was further degassed and stirred at 105°C for 16 hr. The reaction mixture was allowed to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated 131
2015268744 15 Dec 2015 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:l—>4:1) to give the title compound as pale-yellow crystals (yield 150 mg, 69%) .
1H-NMR (CDC13)5: 2.38 (3H, s) , 6.94-6.95 (1H, m) , 7.21-7.31 (2H, m), 7.39-7.42 (1H, m) , 7.48-7.53 (2H, m), 9.85 (1H, s), 9.95 (1H, br).
Reference Example 149 io 5-(2-bromophenyl)-lH-pyrrole-3-carbaldehyde
By a similar operation as in Reference Example 148 and using 5-bromo-lH-pyrrole-3-carbaldehyde (870 mg), (2bromophenyl)boronic acid (1.20 g), sodium carbonate (1.27 g) and tetrakis(triphenylphosphine)palladium (289 mg), the title compound was obtained as colorless crystals (yield 396 mg,
32%) .
’’H-NMR (CDC13)5: 6.94-6.95 (1H, m) , 7.16-7.22 (1H, m) , 7.347.39 (1H, m), 7.49-7.54 (2H, m), 7.63-7.66 (1H, m), 9.28 (1H, br), 9.85 (1H, s).
Reference Example 150
5-[2-(methylsulfinyl)phenyl]-lH-pyrrole-3-carbaldehyde
To a solution of 5-[2-(methylthio)phenyl]-lH-pyrrole-3carbaldehyde (200 mg) in ethyl acetate (10 mL) was added 3chloroperbenzoic acid (238 mg) under ice-cooling. After stirring at room temperature for 1 hr, a saturated sodium thiosulfate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound as a palepink powder (yield 160 mg, 75%).
’’H-NMR (CDC13)5: 2.64 (3H, s) , 7.04-7.06 (1H, m) , 7.35-7.41 (1H, m), 7.57-7.64 (2H, m), 7.72-7.82 (2H, m), 9.86 (1H, s),
12.35 (1H, br).
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Reference Example 151
5-[2-(methylsulfonyl)phenyl]-lH-pyrrole-3-carbaldehyde
To a solution of 5-[2-(methylthio)phenyl]-lH-pyrrole-3carbaldehyde (100 mg) in ethyl acetate (5 mL) was added 35 chloroperbenzoic acid (318 mg) under ice-cooling. After stirring at room temperature for 3 hr, a saturated sodium thiosulfate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous io sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l:l-»l:3) to give the title compound as pale-yellow crystals (yield 88.9 mg, 78%).
1H-NMR (CDC13)5: 2.77 (3H, s) , 6.94-6.96 (1H, m) , 7.54-7.60 (2H, m), 7.67-7.73 (2H, m), 8.20-8.24 (1H, m), 9.88 (1H, s),
10.60 (1H, s).
Reference Example 152
5-(2-fluorophenyl)-4-iodo-lH-pyrrole-3-carbaldehyde
5-(2-Fluorophenyl)-lH-pyrrole-3-carbaldehyde (2.0 g) was dissolved in N,N-dimethylformamide (60 mL), N-iodosuccinimide (2.38 g) was added and the mixture was stirred at for 12 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate solution, a 3% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3->l:1) to give the title compound as a pale-brown powder (yield 450 mg, 14%).
•‘H-NMR (CDC13)5: 7.16-7.30 (2H, m) , 7.37-7.44 (1H, m) , 7.63 (1H, d, J=3.4 Hz), 7.81-7.86 (1H, m), 9.24 (1H, br) , 9.81 (1H, s) · .
Reference Example 153
5-mesityl-l- (pyridin-3-ylsulfonyl) -lH-pyrrole-3-carbaldehyde 133
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To a solution of 5-mesityl-lH-pyrrole-3-carbaldehyde (0.36 g) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 0.14 g) under ice-cooling, and the mixture was stirred at room temperature for 0.5 hr. A solution of 155 crown-5 (0.75 g) in tetrahydrofuran (3 mL) was added and, after stirring for 5 min, pyridin-3-ylsulfonyl chloride (0.45 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 0.5 hr, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction io mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1—>2:1) to give the title is compound as a pale-brown amorphous form (yield 0.38 g, 62%). H-NMR (CDC13)5: 1.63 (6H, s) , 2.35 (3H, s) , 6.48 (1H, d, J=1.5 Hz), 6.83 (2H, s), 7.26-7.35- (1H, m), 7.60-7.64 (1H, m) , 8.17 (1H, dd, 0=1.5, 0.9 Hz), 8.56 (1H, d, J=2.1 Hz), 8.83 (1H, dd, J=4.5, 1.5Hz), 9.90 (1H, s).
Reference Example 154
5-[2-(methylthio)phenyl]-1-(pyridin-3-ylsulfonyl)-lH-pyrrole3-carbaldehyde
To a suspension of sodium hydride (60% in oil, 40 mg) in tetrahydrofuran (3 mL) were added a solution of 5—[2— (methylthio) phenyl]-lH-pyrrole-3-carbaldehyde (150 mg) in tetrahydrofuran (5 mL), 15-crown-5 (182 mg) and pyridin-3ylsulfonyl chloride (135 mg) under ice-cooling. After stirring at room temperature for 2 hr, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:l-»2:1) to give the title compound as colorless crystals (yield 170 mg, 69%).
H-NMR (CDC13)5: 2.05 (3H, s) , 6.68 (1H, d, J=2.1 Hz), 6.97134
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6.99 (1H, m), 7.17-7.31 (3H, m) , 7.40-7.45 (1H, m) , 7.65-7.70 (1H, m), 8.16 (1H, d, J=2.1 Hz), 8.45-8.46 (1H, m), 8.75-8.77 (1H, m), 9.90 (1H, s).
Reference Example 155
5-(2-bromophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carbaldehyde
By a similar operation as in Reference Example 154 and using sodium hydride (60% in oil, 91.0 mg), 5-(2-bromophenyl)lH-pyrrole-3-carbaldehyde (396 mg), 15-crown-5 (418 mg) and io pyridin-3-ylsulfonyl chloride (309 mg), the title compound was obtained as a pale-yellow solid (yield 560 mg, 91%).
^i-NMR (CDC13)5: 6.66 (1H, d, J=1.5 Hz), 7.31-7.40 (4H, m) , 7.48-7.52 (1H, m),' 7.66-7.71 (1H, m) , 8.15 (1H, d, J=1.8 Hz), 8.55 (1H, d, J=2.7 Hz), 8.82-8.84 (1H, m), 9.92 (1H, s).
Reference Example 156
5-[2-(methylsulfonyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1Hpyrrole-3-carbaldehyde , By a similar operation as in Reference Example 154 and using sodium hydride (60% in oil, 40 mg), 5-(220 (methylsulfonyl)phenyl]-lH-pyrrole-3-carbaldehyde (88.9 mg), 15-crown-5 (94.4 mg) and pyridin-3-ylsulfonyl chloride (69.7 mg), the title compound was obtained as a colorless amorphous form (yield 72.0 mg, 52%).
1H-NMR (CDC13)6: 2.87 (3H, s), 6.67 (1H, d, J=1.8 Hz), 7.3725 7.48 (2H, m), 7.72-7.76 (3H, m), 8.02-8.05 (1H, m), 8.14 (1H, d, J=1.8 Hz), 8.50 (1H, d, J=2.7 Hz), 8.81-8.83 (1H, m) , 9.89 (1H, s).
Reference Example 157
2-[4-formyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-230 yl]benzonitrile .
A suspension of 5-(2-bromophenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrole-3-carbaldehyde (102 mg), zinc cyanide (61.0 mg) and tetrakis(triphenylphosphine)palladium (60.0 mg) in Ν,Ν-dimethylformamide (2 mL) was heated (100 W, 4 min 30 sec) using a microwave focused chemical synthesis reactor 135
2015268744 15 Dec 2015 manufactured by CEM, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:
hexane-ethyl acetate=4:l->2:1) to give the title compound as a pale-yellow oil (yield 97.4 mg, 63%).
1H-NMR (CDC13)5: 6.79 (1H, d, J=1.8 Hz), 7.41-7.51 (2H, m), 7.58-7.-78 (4H, m) , 8.17 (1H, d, J=l-.5 Hz), 8.45 (1H, d, J=2.7
Hz), 8.84-8.86 (1H, m), 9.91 (1H, s) .
Reference Example 158
5-(2-fluorophenyl)-4-iodo-l-(pyridin-3-ylsulfonyl)-lH-pyrrole3-carbaldehyde
To a solution (42 mL) of 5-(2-fluorophenyl)-4-iodo-lH15 pyrrole-3-carbaldehyde (400 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 102 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (560 mg) was added dropwise and the mixture was stirred for 30 min. Pyridin-3-ylsulfonyl chloride (340 mg) was added, and the mixture was further stirred for 1 hr. The reaction mixture was diluted with saturated brine and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2-»l:1) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 540 mg, 93%) .
1H-NMR (CDC13)5: 7.01-7.07 (1H, m) , 7.12-7.17 (1H, m) , 7.2330 7.28 (1H, m), 7.37-7.41 (1H, m), 7.50-7.58 (1H, m) , 7.69-7.73 (1H, m), 8.21 (1H, s), 8.54-8.54 (1H, m), 8.85 (1H, dd, J=4.9, 1.5 Hz), 9.85 (1H, S).
Reference Example 159
5-(2,6-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrole-335 carbaldehyde
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A mixture of 5-bromo-lH-pyrrole-3-carbaldehyde (0.87 g),
2, 6-dimethylphenylboronic acid (4.50 g), cesium carbonate (13.0 g), tri-tert-butylphosphine (0.10 g), tris(dibenzylideneacetone)dipalladium (0) (0.23 g) and mesitylene (200 mL) was stirred with heating under reflux for hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified io by silica gel column chromatography (eluent: hexane-ethyl acetate=3:l) to give a brown oil (0.48 g) . To a solution of the oil in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 0.19 g) under - ice-cooling, and the mixture was stirred at room temperature for 0.5 hr. A solution of 1515 crown-5 (1.06 g) in tetrahydrofuran (3 mL) was added, and the mixture was stirred for 5 min. Pyridin-3-ylsulfonyl chloride (0.64 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 0.5 hr, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:l) to give the title compound as a pale-brown oil (yield 0.42 g, 25%).
’H-NMR (CDC13)6: 1-66 (6H, s), 6.52 (1H, d, J=2.1 Hz), 6.70 (2H, d, J=7.5 Hz), 7.25-7.34 (2H, m), 7.56-7.60 (1H, m), 8.19 (1H, d, J=1.5 Hz), 8.53 (1H, d, J=1.8 Hz), 8.81-8.83 (1H, m), 9.91 (1H, s).
Reference Example 160
2-bromo-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrole-3-carbaldehyde
5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carbaldehyde (330 mg) was dissolved in Ν,Ν-dimethylformamide (30 mL), N-bromosuccinimide ¢356 mg) was added and the mixture
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2015268744 15 Dec 2015 was stirred at 80°C for 2 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 270 mg, 66%).
1H-NMR (CDC13)5: 6.70 (1H, s) , 7.12-7.26 (2H, m) , 7.29-7.35 (1H, m), 7.44-7.52 (2H, m) , 8.07-8.11 (1H, m), 8.89 (1H, dd, J=4.9, 1.5 Hz), 9.01-9.02 (1H, m), 9.86 (1H, s).
Reference Example 161
2-(2-fluorophenyl)-4-formyl-l-(pyridin-3-ylsulfonyl)-1H25 pyrrole-3-carbonitrile
5-(2-Fluorophenyl)-4-iodo-l-(pyridin-3-ylsulfonyl)-1Hpyrrole-3-carbaldehyde (489 mg), copper (I) cyanide (480 mg), tris(dibenzylideneacetone)dipalladium (0) (49 mg) and 1,1' bis(diphenylphosphino)ferrocene (89 mg) were mixed in 1,420 dioxane (20 mL), and the mixture was heated under reflux for 3 hr. The reaction mixture was allowed to cool, diluted with ethyl acetate, and filtered. The obtained filtrate was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:3—>3:7) to give the title compound as a colorless oil (yield 380 mg, about 100%).
'H-NMR (CDC13)5: 7.06-7.12 (1H, m), 7.24-7.32 (2H, m) , 7.4030 7.45 (1H, m), 7.55-7.63 (1H, m), 7.70-7.74 (1H, m), 8.19 (1H,
S) , 8.57 (1H, d, J=1.9 Hz), 8.88 (1H, dd, J=4.8, 1.6 Hz), 9.97 (1H, s).
Reference Example 162
5-(2-fluorophenyl)-3-formyl-l-(pyridin-3-ylsulfonyl)-1H35 pyrrole-2-carbonitrile
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2-Bromo-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrole-3-carbaldehyde (340 mg), copper (I) cyanide (400 mg), tris(dibenzylideneacetone)dipalladium (0) (40 mg), 1,1'bis(diphenylphosphino)ferrocene (70 mg) were mixed in 1,45 dioxane (30 mL), and the mixture was heated under reflux for 24 hr. The reaction mixture was allowed to cool, diluted with ethyl acetate, and filtered. The obtained filtrate was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and io concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 169 mg, 57%). XH-NMR (CDC13)6: 6.72 (1H, s) , 7.12-7.18 (1H, m) , 7.24-7.28 (2H, m), 7.50-7.60 (2H, m), 8.10-8.14 (1H, m), 8.82 (1H, d,
J=2.4 Hz), 8.92 (1H, dd, J=4.9, 1.5 Hz), 10.09 (1H, s). Reference Example 163 tert-butyl ({5-bromo-l-[(6-methoxypyridin-3-yl)sulfonyl]-1Hpyrrol-3-yl}methyl)methylcarbamate
Sodium hydride (60% in oil, 433 mg) was washed twice with hexane, and suspended in tetrahydrofuran (20 mL) . A solution of tert-butyl [(5-bromo-lH-pyrrol-3-yl)methyl]methylcarbamate (2.66 g) in tetrahydrofuran (10 mL) was added to the suspension at 0°C, and a solution of 15-crown-5 (2.20 mL) and
6-methoxypyridin-3-ylsulfonyl chloride (2.29 g) in tetrahydrofuran (5 mL) was added at the same temperature.
After stirring at room temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:l) to give the title compound as a brown oil (yield 4.02 g, 95%).
XH-NMR (CDC13)5: 1-47 (9H, s) , 2.79 (3H, brs) , 4.01 (3H, s) ,
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4.17 (2H, brs), 6.25 (1H, brs), 6.82 (1H, d, J=9.0Hz), 7.32 (1H, brs), 7.94-7.98 (1H, m) , 8.77-8.78 (1H, m) .
Reference Example 164 tert-butyl {[5-(4-cyanophenyl) -1-(pyridin-3-ylsulfonyl)-1H5 pyrrol-3-yl]methyl}methylcarbamate
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-IH-pyrrol 3-yl ] methyl }methyl carbamate (430 mg), (4-cyanophenyl)boronic acid (176 mg), sodium carbonate (254 mg) and io tetrakis(triphenylphosphine)palladium (57.8 mg), the title compound was obtained as a pale-yellow oil (yield 382 mg,
84%) .
1H-NMR (CDC13)5: 1.46 (9H, s) , 2.79 (3H, s) , 4.21 (2H, brs), 6.23 (1H, brs), 7.28-7.34 (2H, m), 7.39-7.43 (2H, m) , 7.5915 7.66 (3H, m), 8.55 (1H, d, J=2.1 Hz), 8.74-8.76 (1H, m). Reference Example 165 tert-butyl {[5-(5-cyano-2-fluorophenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-IH-pyrrol 3-yl]methyl}methylcarbamate (430 mg) , (5-cyano-2fluorophenyl)boronic acid (198 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (57.8 mg), the titl compound was obtained as a pale-yellow oil (yield 28.9 mg,
6%) .
1H-NMR (CDC13)5: 1-46 (9H, s) , 2.82 (3H, s) , 4.24 (2H, brs), 6.28 (1H, brs), 7.21 (1H, t, J=8.7 Hz), 7.35-7.42 (2H, m), 7.49-7.52 (1H, m) , 7.69-7.73 (2H, m), 8.66 (1H, d, J=2.4 Hz), 8.81-8.83 (1H, m).
Reference Example 166 tert-butyl { [5-(2-fluoro-5-methoxyphenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate tert-Butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-IH-pyrrol 3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-535 methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate 140
2015268744 15 Dec 2015 (253 mg) and tetrakis(triphenylphosphine)palladium (174 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 90°C for 1 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column io chromatography (eluent: hexane-ethyl acetate=l:l) to give the title compound as a colorless oil (yield 475 mg, about 100%) . “H-NMR (CDC13)5: 1.47 (9H, s) , 2.83 (3H, s) , 3.78 (3H, s) , 4.24 (2H, s), 6.22 (1H, d, J=l.l Hz), 6.69-6.71 (1H, m) , 6.90-6.98 (2H, m), 7.72-7.36 (2H, m), 7.69-7.73 (1H, m), 8.65 (1H, d,
J=2.3 Hz), 8.77 (1H, dd, J=4.9, 1.5 Hz).
Reference Example 167 tert-butyl {[5-(2-fluoro-3-formylphenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methylJmethylcarbamate
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]methyl}methylcarbamate (430 mg), (2-fluoro-3formylphenyl)boronic acid (252 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (173 mg), the title compound was obtained as a pale-yellow oil (yield 250 mg,
53%) .
“Ή-NMR (CDC13)5: 1.47 (9H, s), 2.83 (3H, s) , 4.25 (2H, brs), 6.28 (1H, brs), 7.26-7.46 (4H, m), 7.68-7.72 (1H, m), 7.927.97 (1H, m), 8.61 (1H> d, J=2.1 Hz), 8.77-8.79 (1H, m), 10.30 (1H, s).
Reference Example 168 tert-butyl {[5-(3-acetyl-2-fluorophenyl)-1-(pyridin-3ylsulfony1) -ΙΗ-pyrrο1-3-y1]methyl}methylcarbamate
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-IH-pyrrol35 3-yl]methylJmethylcarbamate (430 mg) , (3-acetyl-2141
2015268744 15 Dec 2015 fluorophenyl)boronic acid (273 mg), sodium carbonate (254 mg), and tetrakis(triphenylphosphine)palladium (173 mg), the title compound was obtained as a pale-yellow oil (yield 443 mg,
91%) .
^-NMR (CDC13)5: 1.47 (9H, s) , 2.59 (3H, d, J=5.4 Hz), 2.83 (3H, s), 4.25 (2H, brs), 6.24 (1H, brs), 7.19-7.36 (4H, m), 7.66-7.70 (1H, m), 7.90-7.96 (1H, m), 8.60 (1H, d, J=2.4 Hz), 8.76-8.78 (1H, m).
Reference Example 169 io tert-butyl {[5-(2-fluoropyridin-3-yl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate
A suspension of tert-butyl {[5-bromo-l-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methylJmethylcarbamate (430 mg), (2-fluoropyridin-3-yl)boronic acid (221 mg), sodium carbonate is (254 mg) and tetrakis(triphenylphosphine)palladium (173 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was stirred at 105°C for 1 hr. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1_»1:1) to give the title compound as a pale-yellow oil (yield 310 mg, 69%).
1H-NMR (CDC13)5: 1.46 (9H, s) , 2.82 (3H, s) , 4.23 (2H, brs),
6.29 (1H, brs) , 7.23-7.27 (1H, m), 7.34-7.39 (2H, m) , 7.66-
7.73 (2H, m), 8.25-8.27 (1H, m), 8.66 (1H, d, J=2 .4 Hz), 8.78
8.80 (1H, m) .
Reference Example 170 tert-butyl {[5-(3-fluoropyridin-4-yl)-1-(pyridin-3ylsulf onyl) -ΙΗ-pyrrol-3-yl]methyl}methylcarbamate tert-Butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]methyl}methylcarbamate (215 mg), (3-fluoropyridin-4yl)boronic acid hydrate (120 mg), sodium hydrogencarbonate (126 mg) and tetrakis(triphenylphosphine)palladium (87 mg)
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2015268744 15 Dec 2015 were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 80°C for 3 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=l:l) to give the io title compound as a pale-yellow oil (yield 60 mg, 27%).
1H-NMR (CDC13)6: 1.47 (9H, s) , 2.61 (3H, s) , 4.24 (2H, s) , 6.35 (1H, s), 7.22-7.26 (1H, m), 7.35-7.40 (2H, m) , 7.71-7.75 (1H, m) , 8.47 (1H, d, J=4.8 Hz), 8.50 (1H, d, J=1.3 Hz), 8.70 (1H, d, J=2.1 Hz), 8.81 (1H, dd, J=4.8, 1.6 Hz).
Reference Example 171 tert-butyl {[5-(2-chloropyridin-3-yl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate tert-Butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-IH-pyrrol3-yl]methyl}methylcarbamate (431 mg), (2-chloropyridin-320 yl)boronic acid (237 mg), sodium hydrogencarbonate (126 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 100°C for 3 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l:1-»1: 4) to give the title compound as a colorless oil (yield 280 mg, 60%). XH-NMR (CDC13)5: 1.47 (9H, s) , 2.84 (3H, s) , 4.27 (2H, s) , 6.30 (1H, s), 7.30-7.39 (3H, m), 7.65-7.73 (2H, m), 8.43-8.45 (1H, m) , 8.67 (1H, d, J=2.3 Hz), 8.80 (1H, dd, J=4.9, 1.5 Hz).
Reference Example 172
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2015268744 15 Dec 2015 tert-butyl {[5-(6-chloropyridin-3-yl)-1-(pyridin-3ylsulfonyl) -lH-pyrrol-3-yl] methyl}methylcarbamate Reference Example 173 tert-butyl {[5-(6'-chloro-2,3'-bipyridin-5-yl)-1-(pyridin-35 ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate tert-Butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]methyl}methylcarbamate (431 mg), (6-chloropyridin-3yl)boronic acid (237 mg), sodium hydrogencarbonate (252 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added io to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL) , and the mixture was stirred under a nitrogen atmosphere at 90°C for 3 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate.
is The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l:l-»3:7), and fractions showing Rf value of 0.6 (eluent: hexane-ethyl acetate=l:l) were collected to give the title compound of
Reference Example 172 as a colorless oil (yield 100 mg, 22%). Then, fractions showing Rf value of 0.4 (eluent: hexane-ethyl acetate=l:l) were collected to give the title compound of Reference Example 173 as a pale-yellow powder (yield 100 mg,
19%) .
Reference Example 172 ’H-NMR (CDC13)5: 1-47 (9H, s), 2.81 (3H, s) , 4.23 (2H, s), 6.24 (1H, s), 7.23-7.38 (3H, m), 7.59-7.63 (1H, m), 7.72 (1H, dd, J=8.3, 2.3 Hz), 8.14 (1H, d, J=2.3 Hz), 8.64 (1H, d, J=2.3 Hz), 8.78 (1H, dd, J=4.7, 1.7 Hz).
Reference Example 173 ^-NMR (CDC13)5: 1.47 (9H, s) , 2.82 (3H, s) , 4.24 (2H, s), 6.29 (1H, s) , 7.31-7.37 (2H, m), 7.47 (1H, d, J=8.3 Hz), 7.64-7.68 (1H, m) , 7.76-7.86 (2H, m) , 8.38 (1H, dd, _J=8.5, 2.5 Hz), 8.51 (1H, d, J=1.9 Hz), 8.63 (1H, d, J=2.3 Hz), 8.77 (1H, dd, J=4.9, 1.5 Hz), 9.04 (1H, d, J=2.3Hz).
Reference Example 174
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2015268744 15 Dec 2015 tert-butyl ({5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-3yl) sulfonyl]-lH-pyrrol-3-yl}methyl)methylcarbamate
By a similar operation as in Reference Example 79 and using tert-butyl ({5-bromo-l-[(6-methoxypyridin-35 yl)sulfonyl]-lH-pyrrol-3-yl}methyl)methylcarbamate (463 mg), (2-fluoropyridin-3-yl)boronic acid (172 mg), sodium carbonate (260 mg) and tetrakis(triphenylphosphine)palladium (176 mg), the title compound was obtained as a pale-yellow oil (yield 293 mg, 45%).
^-NMR (CDC13)5: 1-47 (9H, s), 2.83 (3H, brs), 3.97 (3H, s) ,
4.23 (2H, brs), 6.28 (1H, s), 6.69-6.72 (1H, m) , 7.26-7.36 (2H, m), 7.49-7.53 (1H, m) , 7.75-7.80 (1H, m), 8.22-8.23 (1H, m), 8.26-8.27 (1H, m) .
Reference Example 175 is tert-butyl ({5-[2-fluoro-3-(hydroxymethyl)phenyl]-1-(pyridin3-ylsulfonyl)-lH-pyrrol-3-yl}methyl)methylcarbamate
To a solution of tert-butyl {[5-(2-fluoro-3formylphenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol-3yl]methyl{methylcarbamate (388 mg) in tetrahydrofuran (8 mL) were added under ice-cooling, sodium borohydride (41.3 mg) and methanol (3 mL). After stirring at the same temperature for 30 min, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexaneethyl acetate=2:1->1:2) to give the title compound as a colorless oil (yield 238 mg, 61%).
XH-NMR (CDC13)8: 1.46 (9H, s), 2.83 (3H, s) , 4.24 (2H, brs),
4.65 (2H, brs), 6.19 (1H, brs), 7.15-7.19 (2H, m), 7.34-7.38 (2H, m), 7.51-7.55 (1H, m) , 7.73-7.76 (1H, m) , 8.40-8.41 (1H, m), 8.75-8.77 (1H, m), 1H not detected.
Reference Example 176 tert-butyl ({5-[2-fluoro-3-(1-hydroxyethyl)phenyl]-1-(pyridin35 3-ylsulfonyl)-lH-pyrrol-3-yl}methyl)methylcarbamate 145
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By a similar operation as in Reference Example 175 and using tert-butyl {[5-(3-acetyl-2-fluorophenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methylJmethylcarbamate (443 mg), the title compound was obtained as a pale-yellow amorphous form (yield 318 mg, 71%).
H-NMR (CDC13)5: 1.47 (9H, s) , 1.50 (3H, d, J=6.3 Hz), 2.83 (3H, s), 4.25 (2H, brs), 5.06 (1H, q, J=6.3 Hz), 6.20 (1H, brs), 7.09-7.22 (2H, m), 7.34-7.38 (2H, m), 7.59-7.64 (1H, m), 7.72-7.76 (1H, m), 8.40 (1H, d, J=2.4 Hz), 8.75-8.78 (1H, m) , ίο 1H not detected.
Reference Example 177 tert-butyl {[5-(2-fluoro-3-methoxyphenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate tert-Butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol15 3-yl]methyl[methylcarbamate (431 mg) , (2-fluoro-3methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (88 mg) were added to a mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere 100°C for 2 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l:l) to give the title compound as a colorless oil (yield 475 mg, about 100%). H-NMR (CDC13)5: 1.46 (9H, s) , 2.82 (3H, s) , 3.90 (3H, s) , 4.24 (2H, s), 6.21 (1H, d, J=1.5Hz), 6.72-6.79 (1H, m), 7.00-7.09 (2H, m), 7.32-7.36 (2H, m), 7.69-7.73 (1H, m), 8.63 (1H, d, J=2.3 Hz), 8.76 (1H, dd, J=4.9, 1.5 Hz).
Reference Example 178 tert-butyl {[5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methyl[methylcarbamate tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-IH-pyrrol146
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3-yl]methylJmethylcarbamate (431 mg) , (2-fluoro-6methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (176 mg) were added to a mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 100°C for 20 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried io over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l:l) to give the title compound as a colorless oil (yield 100 mg,
21%) .
1H-NMR (CDC13)5: 1-46 (9H, s) , 2.85 (3H, s) , 3.58 (3H, s) , 4.26 (2H, s), 6.17 (1H, d, J=1.9Hz), 6.64-6.70 (2H, m), 7.31-7.39 (3H, m), 7.71-7.75 (1H, m), 8.60 (1H, d, J=1.9 Hz), 8.76 (1H, dd, J=4.9, 1.5 Hz).
Reference Example 179
2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-l,3,2dioxaborolane
A solution (10 mL) of l-bromo-4-(difluoromethoxy)benzene (500 mg), 4,4,4',4',5,5,5',5'-octamethyl-2, 2'-bi-1,3,2dioxaborolane (654 mg), potassium acetate (660 mg) and 1,1'25 bis(diphenylphosphino)ferrocene dichloropalladium (73.2 mg) in dimethyl formamide was stirred at 80°C for 3 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1_>8:1) to give the title compound as a pale-yellow oil (yield 348 mg, 58%).
1H-NMR ,(CDC13)5: 1.35 (12H, s) , 6.54 (1H, t, J=73.5Hz), 7.09 (2H, d, J=7.8 Hz), 7.81 (2H, d, J=7.8 Hz).
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Reference Example 180 tert-butyl ({5-[4- (difluoromethoxy)phenyl]-1-(pyridin-3ylsulfonyl) -lH-pyrrol-3-yl}methyl)methylcarbamate tert-Butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-IH-pyrrol5 3-yl]methyl}methylcarbamate (430 mg), 2— [4— (difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-l,3,2dioxaborolane (348 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (174 mg) were suspended in dimethoxyethane (10 mL) and water (4 mL), and the mixture io was stirred under a nitrogen atmosphere at 105°C for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1_>2:1) to give the title compound as a pale-yellow oil (yield 550 mg, quantitative yield).
1H-NMR (CDC13)5: 1-46 (9H, s), 2.80 (3H, s) , 4.21 (2H, brs),
6.13 (1H, brs), 6.57 (1H, t, J=73.2 Hz), 7.06-7.09 (2H, m), 7.21-7.31 (4H, m) , 7.55-7.59 (1H, m), 8.54 (1H, d, J=2.4 Hz), 8.71-8.73 (1H, m).
Reference Example 181 tert-butyl methyl{ [5-(4-methylpyridin-3-yl)-1-(pyridin-325 ylsulfonyl)-lH-pyrrol-3-yl]methyl}carbamate tert-Butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-IH-pyrrol3-ylJmethyl}methylcarbamate (431 mg) , (4-methylpyridin-3yl)boronic acid (206 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 80°C for 6 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, dried over
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2015268744 15 Dec 2015 anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l:l_>0:1) to give the title compound as a colorless oil (yield 230 mg, 52%).
1H-NMR (CDC13)5: 1-47 (9H, s) , 2.11 (3H, s) , 2.85 (3H, s) , 4.27 (2H, s), 6.15 (1H, s), 7.18 (1H, d, J=4.9 Hz), 7.34-7.39 (2H, m), 7.58-7.62 (1H, m), 7.94 (1H, s) , 8.49 (1H, d, J=5.3 Hz), 8.64 (1H, d, J=2.3 Hz), 8.80 (1H, dd, J=4.9, 1.5 Hz).
Reference Example 182 io 3-bromo-2-methylpyridine
2-Methylpyridine (46.6 g) was added dropwise to aluminum chloride (200 g) and the mixture was stirred at 100°C. To a mixture was added dropwise bromine (40.0 g) at the same temperature over 1 hr, and the mixture was further stirred for
30 min. After cooling, the reaction mixture was poured into ice water, concentrated hydrochloric acid was added until the mixture was acidified. The obtained solution was washed with ethyl acetate, and the aqueous layer was basified with a 8 mol/L aqueous sodium hydroxide solution. After extraction with diethyl ether, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-diethyl ether=10:l) to give the title compound as a colorless oil (yield 5.09 g,
12%) .
1H-NMR (CDC13)5: 2.67 (3H, s) , 6.98-7.03 (1H, m) , 7.78-7.82 (1H, .m), 8.40-8.44 (1H, m) .
Reference Example 183 tert-butyl methylf[5-(2-methylpyridin-3-yl)-1-(pyridin-330 ylsulfonyl)-lH-pyrrol-3-yl]methyl}carbamate
To a solution of 3-bromo-2-methylpyridine (504 mg) in diethyl ether (15 mL) was added a 1.62 mol/L solution (2 mL) of n-butyl lithium in hexane at -78°C, and the mixture was stirred at the same temperature for 15 min. Thereto was added triisopropoxyborane (1.22 mL) at the same temperature, and the 149
2015268744 15 Dec 2015 obtained mixture was stirred at 0°C for 1 hr. Methanol (2 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure, tert-Butyl ({5-bromo-l[(pyridin-3-yl)sulfonyl]-lH-pyrrol-3-yl}methyl)methylcarbamate {432 mg), sodium carbonate (1.15 g), tetrakis(triphenylphosphine)palladium (174 mg), 1,2dimethoxyethane (20 mL) and water (10 mL) was added to the residue, and the mixture was stirred under a nitrogen atmosphere at 105°C for 1 hr. The reaction mixture was allowed io to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=l:1) to give the title compound as a brown oil (yield 282 mg, 22%).
1H-NMR (CDC13)5: 1.47 (9H, s) , 2.09 (3H, s) , 2.85 (3H, s) , 4.27 (2H, brs), 6.14 (1H, brs), 7.10-7.14 (1H, m) , 7.26-7.38 (3H,
m), 7.56-7.60 (1H, m), 8.54-8.56 (1H, m), 8.60-8.61 (1H, m), 8.78-8.80 (1H, m).
Reference Example 184 6-methylnicotinamide
A mixture of methyl 6-methylnicotinate (13.9 g) and 28% aqueous ammonia (140 mL) was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 8.98 g, 72%). 1H-NMR (CDC13)5: 2.63 (3H, s) , 5.60-6.20 (2H, brm) , 7.25-7.28 (1H, m), 8.04-8.07 (1H, m), 8.90 (1H, d, J=2.1 Hz).
Reference Example 185 6-methylpyridine-3-amine
Bromine (1.0 mL) was added to a 4 mol/L aqueous sodium hydroxide solution (60 mL) at 0°C, and the mixture was stirred at the same temperature for 15 min. 6-Methylni cot inamide (2.4 150
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g) was added to the obtained solution over 10 min, and the mixture was stirred at room temperature for 30 min and further stirred at 75°C for 4 hr. The reaction mixture was allowed to cool to room temperature, and extracted with ethyl acetate:THF=2:1. The extract was washed with a small amount of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound as a pale-yellow solid (yield 0.93 g, 49%) .
1H-NMR (CDC13)5: 2.43 (3H, s) , 3.54 (2H, brs), 6.89-6.95 (2H, m) , 7.99-8.01 (1H, m).
Reference Example 186 6-methylpyridin-3-ylsulfonyl chloride
To a mixture of 6-methylpyridine-3-amine (449 mg) and concentrated hydrochloric acid (5 mL) was added a solution of sodium nitrite (857 mg) in water (2 mL) at 0°C, and the mixture was stirred at the same temperature for 10 min. To the mixture was added a solution of concentrated hydrochloric acid (2.5 mL), copper sulfate (69 mg) and sodium hydrogen sulfite (5.08
g) in water (8 mL) at 0°C, and the mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1) to give the title compound as a pale-yellow solid (yield 0.12 g, 15%).
1H-NMR (CDC13)5: 2.73 (3H, s) , 7.40-7.43 (1H, m) , 8.16-8.20 (1H, m) , 9.11-9.12 (1H, m) .
Reference Example 187 tert-butyl ({5-bromo-l-[(6-methylpyridin-3-yl)sulfonyl]-1Hpyrrol-3-yl}methyl)methylcarbamate
To a solution of tert-butyl [(5-bromo-lH-pyrrol-3yl)methyl]methylcarbamate (207 mg) in tetrahydrofuran (30 mL) was added sodium hydride (60% in oil, 31 mg) at 0°C, and the 151
2015268744 15 Dec 2015 mixture was stirred at the same temperature for 10 min. A solution (3 mL) of 15-crown-5 (0.16 mL) and 6-methylpyridin-3ylsulfonyl chloride (117 mg) in tetrahydrofuran was added at the same temperature. After stirring at room temperature for
30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The io residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:l) to give the title compound as a brown oil (yield 213 mg, 79%) .
1H-NMR (CDC13)5: 1.47 (9H, s) , 2.66 (3H, s) , 2.79 (3H, s) , 4.17 (2H, brs), 6.26 (1H, brs), 7.26-7.33 (2H, m) , 8.03-8.07 (1H,
m), 9.01-9.02 (1H, m).
Reference Example 188 tert-butyl ({5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3yl)sulfonyl]-lH-pyrrol-3-yl}methyl)methylcarbamate
A suspension of tert-butyl ({5-bromo-l-[(6-methylpyridin20 3-yl) sulfonyl]-lH-pyrrol-3-yl}methyl)methylcarbamate (206 mg), (2-fluoropyridin-3-yl)boronic acid (80 mg), sodium carbonate (119 mg) and tetrakis(triphenylphosphine)palladium (80 mg) in 1,2-dimethoxyethane (5 mL) and water (2.5 mL) was stirred under a nitrogen atmosphere at 105°C for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l:l) to give the title compound as a pale-yellow oil (yield 87 mg,
41%) .
1H-NMR (CDC13)5: 1.46 (9H, s), 2.62 (3H, m) , 2.82 (3H, s) , 4.23 (2H, brs), 6.29 (1H, s), 7.18-7.27 (2H, m), 7.33 (1H, s),
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7.54-7.57 (1H, m), 7.72-7.75 (1H, in), 8.26-8.27 (1H, m) , 8.53 (1H, s).
Reference Example 189
5- (2-fluoropyridin-3-yl)-1-(phenylsulfonyl)-lH-pyrrole-35 carbaldehyde
5-Bromo-l-(phenylsulfonyl)-lH-pyrrole-3-carbaldehyde (3.15 g), (2-fluoropyridin-3-yl)boronic acid (2.83 g), sodium hydrogencarbonate (2.53 g) and tetrakis(triphenylphosphine)palladium (870 mg) were added to a io degassed mixture of 1,2-dimethoxyethane (80 mL) and water (20 mL), and the mixture was stirred under a nitrogen atmosphere at 80°C for 5 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract is was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1_>2:3) to give the title compound as a colorless oil (yield 2.25 g, 68%).
’’H-NMR (CDC13)5: 6.71 (1H, d, J=1.7 Hz), 7.24-7.28 (1H, m) , 7.42-7.48 (4H, m), 7.62-7.68 (1H, m), 7.70-7.76 (1H, m), 8.14 (1H, d, J=1.9 Hz), 8.28-8.31 (1H, m), 9.90 (1H, s).
Reference Example 190
5-(2-fluoropyridin-3-yl)-lH-pyrrole-3-carbaldehyde
5-(2-Fluoropyridin-3-yl)-1-(phenylsulfonyl)-lH-pyrrole-3 carbaldehyde (2.25 g) was dissolved in methanol (20 mL) and tetrahydrofuran (20 mL), a 8 mol/L aqueous sodium hydroxide solution (20 mL) was added dropwise at room temperature and the mixture was stirred for 1 hr. The reaction mixture was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue and insoluble crystals were collected by filtration to give the title compound as pale-brown crystals 153
2015268744 15 Dec 2015 (yield 1.03 g, 79%).
1H-NMR (DMSO-d6)5: 6.99 (1H, d, J=1.5 Hz), 7.43-7.48 (1H, m) , 7.88 (1H, s), 8.12-8.15 (1H, m), 8.27-8.34 (1H, m), 9.77 (1H, s) , 12.28 (1H, brs).
Reference Example 191
4-chloro-5-(2-fluoropyridin-3-yl)-lH-pyrrole-3-carbaldehyde
5-(2-Fluoropyridin-3-yl)-lH-pyrrole-3-carbaldehyde (610 mg) was dissolved in N,N-dimethylformamide (20 mL), Nchlorosuccinimide (641 mg) was added and the mixture was io stirred at 80°C for 40 min. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2_>1:1) to give the title compound as a colorless powder (yield 320 mg, 44%). ’H-NMR (DMSO-d6)5: 7.49-7.54 (1H, m) , 7.86 (1H, d, J=2.3 Hz), 8.12-8.19 (1H, m), 8.30-8.32 (1H, m), 9.80 (1H, s), 12.48 (1H, brs) .
Reference Example 192
4-chloro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrole-3-carbaldehyde
To a solution (20 mL) of 4-chloro-5-(2-fluoropyridin-3yl)-lH-pyrrole-3-carbaldehyde (270 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 100 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (530 mg) was added dropwise and the mixture was stirred for 30 min. 3Pyridylsulfonyl chloride (321 mg) was added, and the mixture was further stirred for 1 hr. The reaction mixture was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l:1-»1:4) , and crystallized from diethyl ether to give the title compound 154
2015268744 15 Dec 2015 as colorless crystals (yield 358 mg, 81%).
XH-]WR (CDC13)5: 7.35-7.39 (1H, m) , 7.42-7.46 (1H, m) , 7.697.73 (1H, m), 7.76-7.82 (1H, m) , 8.14 (1H, s), 8.39-8.41 (1H, m), 8.64 (1H, dd, J=2.5 Hz, 0.6 Hz), 8.89 (1H, dd, J=4.8 Hz,
51.6 Hz), 9.97 (1H, s).
Reference Example 193 tributyl(2-thienyl)stannane
A solution (10 mL) of 2-bromothiophene (1.0 g) in tetrahydrofuran was cooled to -70°C, and a 1.6 mol/L solution io (4.2 mL) of n-butyl lithium in hexane was added dropwise. After stirring at the same temperature for 30 min, tributyltin chloride (2.1 g) was added dropwise. After further stirring for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual oil (2.4 g) containing the title compound was used for the next step without purification.
Reference Example 194 tert-butyl methylf[1-(pyridin-3-ylsulfonyl)-5-(2-thienyl)-1Hpyrrol-3-yl]methyl}carbamate
To a solution of crude tributyl(2-thienyl)stannane (1.1 g) and tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lHpyrrol-3-yl]methyljmethylcarbamate (430 mg) in toluene was added tetrakis(triphenylphosphine)palladium (116 mg), and the mixture was stirred under a nitrogen atmosphere at 120°C for 1 hr. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=4:l) to give the title compound as a pale-yellow oil (yield 315 mg, 73%).
1H-NMR (CDC13)5: 1-47 (9H, s), 2.83 (3H, s), 4.22 (2H, brs), 6.25 (1H, brs), 7.04-7.07 (1H, m) , 7.16-7.17 (1H, m), 7.277.31 (2H, m), 7.36-7.37 (1H, m) , 7.62-7.66 (1H, m), 8.58-8.59 (1H, m), 8.71-8.73 (1H, m) .
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Reference Example 195 ,
3-methyl-2- (tributylstannyl)pyridine
A solution (10 mL) of 2-bromo-3-methylpyridine (1.0 g) in tetrahydrofuran was cooled to -70°C, and a 1.6 mol/L solution (4.0 mL) of n-butyllithium in hexane was added dropwise. After stirring at the same temperature for 15 min, tributyltin chloride (2.2 g) was added dropwise. After further stirring for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was io washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1) to give the title compound as a colorless oil (yield 1.75 g, 79%).
1H-NMR (CDC13)5: 0.85-0.95 (9H, m) , 1.11-1.17 (6H, m) , 1.291.37 (6H, m), 1.49-1.57 (6H, m), 2.36 (3H, s), 6.99-7.03 (1H, m) , 7.31-7.34 (1H, m), 8.52-8.54 (1H, m) .
Reference Example 196 tert-butyl methyl{[5-(3-methylpyridin-2-yl)-1-(pyridin-320 ylsulfonyl)-lH-pyrrol-3-yljmethyl}carbamate
A solution of 3-methyl-2-(tributylstannyl)pyridine (1.0
g),, tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-3yl]methyljmethylcarbamate (563 mg) and tetrakis(triphenylphosphine)palladium (454 mg) in toluene was stirred under a nitrogen atmosphere at 120°C for 30 hr. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=4:l) to give the title compound as a colorless oil (yield 129 mg, 22%).
1H-NMR (CDC13)5: 1.45 (9H, s), 2.80 (3H, brs), 4.25 (2H, brs), 6.26 (1H, brs), 7.23-7.27 (2H, m), 7.39-7.44 (1H, m), 7.60 (1H, d, J=6.9 Hz), 7.99-8.03 (1H, m), 8.36 (1H, d, J=4.5 Hz), 8.78-8.80 (1H, m) , 8.86-8.87 (1H, m) .
Reference Example 197
156
2015268744 15 Dec 2015 tert-butyl {[5-{2-fluoro-3-[(hydroxyimino)methyl]phenyl}-l(pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate
To a solution (3 mL) of tert-butyl {[5-(2-fluoro-3formylphenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol-35 yl] methyl} methyl carbamate (182 mg) in 2-propanol were added hydroxylamine hydrochloride (40 mg) and sodium acetate (47 mg) . After stirring at room temperature for 3 hr, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was extracted with ethyl io acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1_>3:1) to give the title compound as a pale-yellow oil (yield 150 mg, 80%).
1 H-NMR (CDC13)5: 1-46 (9H, s) , 2.82 (3H, s) , 4.24 (2H, s) , 6.22 (1H, s), 7.15-7.19 (2H, m) , 7.31-7.35 (2H, m), 7.67-7.71 (1H, m), 7.76-7.85 (1H, m), 8.27 (1H, s), 8.63 (1H, d, J=2.1 Hz), 8.76-8.78 (1H, m), 1H not detected.
Reference Example 198 tert-butyl {[5-(3-cyano-2-fluorophenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methylJmethylcarbamate
To a solution (5 mL) of tert-butyl {[5-{2-fluoro-3[(hydroxyimino)methyl]phenyl}-!-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]methylJmethylcarbamate (150 mg) in tetrahydrofuran were added triethylamine (93 mg) and methanesulfonyl chloride (84 mg) at room temperature. The reaction mixture was stirred at 70°C for 8 hr, and cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1_>3:1) to give the title
compound as a pale-yellow oil (yield 106 mg, 73%) .
1H-NMR (CDC13)5: 1.46 (9H, s) , 2.82 (3H, s) , 4.24 (2H, s), 6.28
35 (1H, brs), 7.25-7.40 (3H, in), 7.48-7.53 157 (1H, m) , 7.66-7.70
2015268744 15 Dec 2015 (2H, m), 8.62 (1H, d, J=2.7 Hz), 8.80-8.82 (1H, in) .
Reference Example 199 tert-butyl {[5-(4-bromo-3-thienyl)-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl ] methyl} methyl carbamate
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-l-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]methyl}methylcarbamate (430 mg), (4-bromo-3thienyl)boronic acid (248 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (116 mg), the title io compound was obtained as a pale-yellow oil (yield 470 mg,
92%) .
1 H-NMR (CDC13)5: 1-47 (9H, s) , 2.84 (3H, brs), 4.26 (2H, brs), 6.21-6.22 (1H, m) , 7.18-7.19 (1H, m), 7.30-7.39 (3H, m), 7.637.67 (1H, m), 8.57-8.58 (1H, m), 8.74-8.76 (1H, m).
Reference Example 200 tert-butyl {[5-(4-cyano-3-thienyl)-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl ] methyl} methyl carbamate
To a solution (5 mL) of tert-butyl {[5-(4-bromo-3thienyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol-320 yl]methyl}methylcarbamate (470 mg) in Ν,Ν-dimethylformamide were added zinc cyanide (215 mg) and tetrakis(triphenylphosphine)palladium (212 mg) and the mixture was sufficiently degassed. The mixture was stirred with heating at 120°C for 18 hr and cooled to room temperature.
25· Water and ethyl acetate were added and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1->2:1) to give the title compound as a pale-yellow oil (yield 297 mg, 71%).
1H-NMR (CDC13)5: 1.47 (9H, s) , 2.83 (3H, brs), 4.25 (2H, brs), 6.34-6.35 (1H, m) , 7.35-7.39 (2H, m) , 7.48 (1H, br) , 7.65-7.'68 (1H, m), 7.87 (1H, d, J=3.0 Hz), 8.53-8.54 (1H, m) , 8.78-8.79
158
2015268744 15 Dec 2015 (1H, m).
Example 1
N-methyl-1-[5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-3yl]methanamine dihydrochloride
5-Phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carbaldehyde (230 mg) was dissolved in absolute tetrahydrofuran (10 mL), a 2 mol/L solution (1 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was io added to a solution of sodium borohydride (76 mg) in methanol (5 mL) , and the mixture was stirred at the same temperature for 20 min. The reaction mixture was diluted with ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetatemethanol=l:0_»l: 1) and further by HPLC (ODS, 0.1% trifluoroacetic acid-containing water-0.1% trifluoroacetic acid-containing acetonitrile=97:3->0.1% trifluoroacetic acidcontaining acetonitrile) to give trifluoroacetate of the title compound. The obtained trifluoroacetate was neutralized with a saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) and ethanol (5 mL) were added, and the mixture was concentrated under reduced pressure and crystallized from ethyl acetate-ethanol to give the title compound (yield 85 mg, 29%) .
1H-NMR (DMSO-d6)0·· 2.50 (3H, s) , 3.97-4.00 (2H, s) , 6.50 (1H, s), 7.14-7.16 (2H, m) , 7.35-7.45 (3H, m), 7.62-7.70 (1H, m),
7.78-7.83 (2H, m) , 8.47-8.48 (1H, m) , 8.84-8.86 (1H, m) , 9.08 159
2015268744 15 Dec 2015 (2H, br), 1H not detected.
Example 2
1—{1—[(6-methoxypyridin-3-yl)sulfonyl]-5-phenyl-lH-pyrrol-3yl}-N-methylmethanamine hydrochloride
1- [ (6-Methoxypyridin-3-yl)sulfonyl]-5-phenyl-lH-pyrrole3-carbaldehyde (59 mg) was dissolved in absolute tetrahydrofuran (5 mL), a 2 mol/L solution (0.25 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was io added to a solution of sodium borohydride (19 mg) in methanol (2 mL), and the mixture was stirred at the same temperature for 20 min. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetatemethanol=l:0_»l: 1) to give a free salt (48 mg) of the title compound. The obtained free salt was dissolved in ethyl acetate (2 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added, and the mixture was left standing at room temperature for 30 min. The precipitated crystals were collected by filtration, washed with ethyl acetate to give the title compound (yield 39 mg, 58%).
1H-NMR (DMSO-d6)5: 2.50 (3H, s) , 3.90 (3H, s) , 3.98 (2H, s) ,
6.45 (1H, s), 6.91-6.94 (1H, m), 7.16-7.18 (2H, m) , 7.36-7.45 (3H, m) , 7.59-7.63 (1H, m), 7.72 (1H, s) , 8.09-8,10 (1H, m), 8.91 (2H, br).
Example 3
N-methyl-l-{l- [6- (methylamino)pyridin-3-ylsulfonyl]-5-phenyl30 lH-pyrrol-3-yl}methanamine dihydrochloride
By a similar reaction as in Example 2 and using 1-(6chloro-3-pyridinesulfonyl)-5-phenyl~lH-pyrrole-3-carbaldehyde (100 mg), the title compound was obtained (yield 58 mg, 47%) . ’’H-NMR (DMSO-d6)6: 2.50 (3H, s) , 2.78 (3H, s) , 3.95-3.99 (2H,
m) , 6.39-6.42 (2H, m), 7.20-7.23 (3H, m), 7.35-7.43 (3H, m),
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7.63 (1H, s), 7.82-7.85 (2H, m) , 9.00 (2H, br), 1H not detected.
Example 4
N-methyl-l-{l-[2-(methylamino)pyridin-3-ylsulfonyl]-5-phenyl5 lH-pyrrol-3-yl }methanamine dihydrochloride
1-(2-Chloropyridin-3-ylsulfonyl)-5-phenyl-lH-pyrrole-3carbaldehyde (173 mg) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution (1.25 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room io temperature for 12 hr. The reaction mixture was added to a solution (2 mL) of sodium borohydride (76 mg) in methanol, and the mixture was stirred at room temperature for 20 min, A saturated aqueous sodium, hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract is was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent: ethyl acetate->ethyl acetate-methanol=l:4) to give a free salt of the title compound. To a solution (3 mL) of the obtained free salt in ethanol was added a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) . The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 126 mg, 59%).
1H-NMR (DMSO-de)5: 2.50 (3H, s'), 2.77 (3H, d, J=4.5 Hz), 3.95-
3.99 (2H, m), 4.80 (1H, br), 6.28-6.30 (1H, m) , 6.41-6.47 (2H,
m) , 7 , .10-7.19 (3H, m), 7.32-7.44 (3H, m) , 7 . 88 (1H, s), 8. ,25-
8.27 (1H, m), 9.19 (2H, br) .
Exarrple 5
3o N-methyl-1-(1- [2- (methylamino) pyrimidin-5-ylsulfonyl] -5phenyl-ΙΗ-pyrro1-3-y1} methanamine hydro chloride
By a similar reaction as in Example 2 and using 1-(2chloropyrimidin-5-ylsulfonyl)-5-phenyl-lH-pyrrole-3carbaldehyde (100 mg), the title compound was obtained (yield
64 mg, 57%) .
161
2015268744 15 Dec 2015 ^-NMR (DMSO-d6)5: 2.50 (3H, s) , 2.80-2.82 (3H, s) , 3.98 (2H, s), 6.47 (1H, s), 7.23-7.26 (2H, m), 7.39-7.43 (3H, m), 7.667.67 (1H, m), 7.96-7.97 (1H, m) , 8.11-8.12 (1H, m) , 8.48-8.52 (1H, m), 8.97 (2H, br).
Example 6
N-methyl-1-[2-methyl-5-phenyl-l-(pyridin-3-ylsulfonyl)-lHpyrrol-3-yl]methanamine dihydrochloride
By a similar reaction as in Example 2 and using 2-methyl 5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde io (235 mg), an ethanol (1 equivalent) adduct of the title compound was obtained as a solid (yield 110 mg, 39%).
1H-NMR (DMSO-d6)5: 1.06 (3H, t, J=7.2 Hz), 2.43-2.50 (6H, m) , 3.44 (2H, dd, J=14.1, 7.2 Hz), 3.91-3.94 (2H, m), 6.47 (1H, s), 7.21-7.43 (2H, m) , 7.36-7.41 (3H, m), 7.56-7.63 (1H, m),
7.82-7.88 (1H, m), 8.53 (1H, s), 8.87-8.93 (3H, m), 2H not detected.
Example 7
N-methyl-1-[1-(2-methylpyrimidin-5-ylsulfonyl)-5-phenyl-lHpyrrol-3-yl]-methanamine dihydrochloride
1- [ (2-Methyl-5-pyrimidine)sulfonyl]-5-phenyl-lH-pyrrole3-carbaldehyde (148 mg) was dissolved in absolute tetrahydrofuran (10 mL), a 2 mol/L solution (1.25 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred overnight at room temperature. The reaction mixture was added to a solution of sodium borohydride (95 mg) in methanol (3.0 mL), and the mixture was stirred at the same temperature for 20 min. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), di-tert-butyl bicarbonate (0.55 g), sodium hydrogencarbonate (0.25 g) and water (10 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed successively with a saturated aqueous sodium 162
2015268744 15 Dec 2015 hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), manganese dioxide (75% chemically treated product, 1.5 g) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column io chromatography (eluent: hexane-ethyl acetate=19:l_>l:l) to give an oil. The obtained oil was dissolved in ethanol (1 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure to give a solid (67 mg) . Recrystallization from ethanol gave the title compound as a colorless solid (yield 34 mg, 18%).
XH-NMR (DMSO-d6)§: 2.53 (3H, s) , 2.70 (3H, s) , 3.98 (2H, s) ,
6.50 (1H, s), 7.18-7.20 (2H, m), 7.38-7.47 (3H, m), 7.76-7.77 (1H, m), 8.59 (2H, s), 8.88 (2H, br), 1H not detected.
Example 8
1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol-3yl]-N-methylmethanamine fumarate
5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carbaldehyde (1.52 g) was dissolved in methanol (30 mL), a 40% methylamine methanol solution (3.57 g) was added at room temperature and the mixture was stirred for 30 min. Sodium borohydride (523 mg) was added at room temperature and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (50 mL) was added and the mixture was stirred for 5 min. The reaction mixture was basified with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=l:0_>7:3) 163
2015268744 15 Dec 2015 to give a free salt of the title compound as a pale-yellow oil (yield 1.30 g) . The obtained free salt (750 mg) was dissolved in ethyl acetate (30 mL), a solution of fumaric acid (278 mg) in methanol (3 mL) was added dropwise at room temperature.
After stirring for 30 min, the obtained crystals were collected by filtration, and washed with ethyl acetate to give the title compound as colorless crystals (yield 912 mg, 74%). ^-NMR (DMSO-d6)5: 2.43 (3H, s), 3.87 (2H, s) , 6.47 (2H, s) ,
6.49 (1H, d, J=1.8Hz), 7.07-7.13 (1H, m) , 7.19-7.26 (2H, m) ,
7.49-7.56 (1H, m) , 7.59-7.64 (1H, m), 7.74 (1H, d, J=1.8 Hz), 7.86-7.90 (1H, m) , 8.56-8.57 (1H, m), 8.87-8.89 (1H, m), 3H not detected.
melting point 201-203°C Example 9
N-methyl-l-{l-(pyridin-3-ylsulfonyl)-5-[2(trifluoromethyl)phenyl]-lH-pyrrol-3-yl}methanamine dihydrochloride
1-(Pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl]lH-pyrrole-3-carbaldehyde (340 mg) was dissolved in ethanol (34 mL), a 40% methylamine methanol solution (695 mg) was added at room temperature and the mixture was stirred for 30 min. Sodium borohydride (102 mg) was added at room temperature and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (10 mL) was added and the mixture was stirred for 5 min.
The reaction mixture was basified with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=l:0-»7:3) and dissolved in ethyl acetate (5 mL) . A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as pale-red crystals (yield 288 mg,
164
2015268744 15 Dec 2015
69%) .
1H-NMR (DMSO-d6)5: 2.47 (3H, t, J=5.5 Hz), 4.00 (2H, t, J=5.5 Hz), 6.60 (1H, d, J=1.8Hz), 7.18-7.21 (1H, m), 7.63-7.81 (4H, m), 7.91-8.00 (2H, m), 8.58 (1H, d, J=1.8 Hz), 8.90-8.92 (1H,
m) , 9.48-9.57 (2H, m), 1H not detected.
Example 10
N-methyl-1-[4-methyl-5-phenyl-l-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]methanamine dihydrochloride
By a similar reaction as in Example 2 and using 4-methyl10 5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde (171 mg) , the title compound was obtained (yield 110 mg, 50%). ^-NMR (DMSO-d6)5·' 1.79 (3H, s) , 2.57 (3H, s) , 3.96-4.00 (2H, m), 6.98-7.01 (2H, m) , 7.36-7.43 (3H, m), 7.55-7.60 (1H, m), 7.79-7.82 (2H, m) , 8.43-8.44 (1H, m), 8.84-8.86 (1H, m), 9.13 (2H, br), 1H not detected.
Example 11
N-methyl-1- [4-methyl-5-phenyl-l- (pyridin-2-ylsulfonyl) -1Hpyrrol-3-yl]methanamine hydrochloride
4-Methyl-5-phenyl-l-(pyridin-2-ylsulfonyl)-lH-pyrrole-320 carbaldehyde (262 mg) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution (1.0 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was added to a solution (5 mL) of sodium borohydride (76 mg) in methanol, and the mixture was stirred at room temperature for 20 min. Water was added, and the mixture was extracted with ethyl acetate.
The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=l:0_»l: 1) and further by HPLC (ODS, 0.1% trifluoroacetic acid-containing water-0.1% trifluoroacetic acid-containing acetonitrile=9:l->0.1% trifluoroacetic acid-containing acetonitrile) to give trifluoroacetate of the title compound.
The obtained trifluoroacetate was neutralized with a saturated 165
2015268744 15 Dec 2015 aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (3 mL), a 4 mol/L solution (2 mL) of hydrogen chloride in ethyl acetate was added. After allowing to stand at room temperature for 30 min, the precipitate was collected by filtration and washed with ethyl acetate to give the title io compound (yield 141 mg, 47%).
“•H-NMR (DMSO-d6)5: 1.79 (3H, s) , 2.59 (3H, s) , 4.01 (2H, s) , 6.88-6.90 (2H, m), 7.27-7.45 (4H, m), 7.71-7.74 (2H, m), 7.957.99 (1H, m), 8.68-8.70 (1H, m), 8.88 (2H, br).
Example 12
1—{1—[(1,2-dimethyl-lH-imidazol-4-yl)sulfonyl]-4-methyl-5phenyl-lH-pyrrol-3-yl}-N-methylmethanamine dihydrochloride
1-[(1,2-Dimethyl-lH-imidazol-4-yl)sulfonyl]-4-methyl-5phenyl-lH-pyrrole-3-carbaldehyde (294 mg) was dissolved in tetrahydrofuran (5 mL), a 2 mol/L solution (1.0 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hr. The mixture was heated to 40°C, and the mixture was further stirred for 4 hr. The reaction mixture was added to a solution (5 mL) of sodium borohydride (76 mg) in methanol, and the mixture was stirred at room temperature for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=9:l_»0:1) to give a free salt of the title compound. To a solution (3 mL) of the obtained free salt in ethyl acetate was added a 4 mol/L hydrogen chlorideethyl acetate solution (1 mL). After allowing to stand at room temperature for 30 min, the precipitate was collected by filtration, and washed with ethyl acetate to give the title 166
2015268744 15 Dec 2015 compound (yield 196 mg, 53%).
XH-NMR (DMSO-d6)5: 1.79 (3H, s) , 2.25 (3H, s) , 2.60 (3H, m) ,
3.45 (3H, s), 3.95-3.99 (2H, m), 4.86 (1H, br) , 6.99-7.01 (2H, m), 7.13 (1H, s), 7.32-7.39 (3H, m), 7.59 (1H, s), 8.96 (2H, br) .
Example 13
1-{1-[(5-chloro-l,3-dimethyl-lH-pyrazol-4-yl)sulfonyl]-4methyl-5-phenyl-lH-pyrrol-3-yl}-N-methylmethanamine hydrochloride io By a similar reaction as in Example 12 and using l—[(5— chloro-1,3-dimethyl-lH-pyrazol-4-yl)sulfonyl]-4-methyl-5phenyl-lH-pyrrole-3-carbaldehyde (378 mg), the title compound was obtained as a solid (yield 238 mg, 55%).
1H-NMR (DMSO-ds)§: 1.67 (3H, s) , 1.79 (3H, s) , 2.58 (3H, s) ,
3.67 (3H, s), 3.99 (2H, s), 6.97-6.99 (2H, m), 7.33-7.41 (3H, m) , 7.73 (1H, s), 8.90 (2H, br).
Example 14 !-{!-[(1,3-dimethyl-lH-pyrazol-4-yl)sulfonyl]-4-methyl-5phenyl-lH-pyrrol-3-yl}-N-methylmethanamine hydrochloride
Using 1-[(5-chloro-l,3-dimethyl-lH-pyrazol-4yl)sulfonyl]-4-methyl-5-phenyl-lH-pyrrole-3-carbaldehyde (295 mg), a free salt (297 mg) of the compound of Example 13 was obtained as an oil. The obtained oil was dissolved in toluene (10 mL) and methanol (10 mL), 10% palladium carbon (50% containing water, 30 mg) and 20% sodium ethoxide-ethanol solution (309 mg) were added, and the mixture was stirred at under a hydrogen atmosphere at room temperature for 24 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate solution (5 mL) and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After allowing to stand at room temperature for 30 min, the precipitate was collected by filtration, and washed with ethyl acetate to give the title compound (yield 221 mg, 72%).
•’•H-NMR (DMSO-d6)5: Ι.θθ (3H, s) , 1.90 (3H, s) , 2.59 (3H, m) ,
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3.63 (3H, s) , 3.99 (2H, s) , 6.99-7.02 (2H, nt), 7.35-7.40 (3H, nt), 7.51 (1H, s), 7.66 (1H, s) , 8.87 (2H, br) .
Example 15
1—{1—[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methyl-55 phenyl-lH-pyrrol-3-yl}-N-methylmethanamine trifluoroacetate
To a solution (1 mL) of 1-[(2,4-dimethyl-l, 3-thiazol-5yl)sulfonyl]-4-methyl-5-phenyl-lH-pyrrole-3-carbaldehyde (27.7 mg) in tetrahydrofuran was added a 2 mol/L solution (0.1 mL) of methylamine in tetrahydrofuran, and the mixture was stirred io at room temperature for 2 hr. The reaction mixture was added to a solution (1 mL) of sodium borohydride (7.6 mg) in methanol, and the mixture was stirred at room temperature for 20 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by HPLC (ODS, 0.1% trifluoroacetic acid-containing water-0.1% trifluoroacetic acid-containing acetonitrile (97:3)-»0.1% trifluoroacetic acid-containing acetonitrile alone), and triturated with diisopropyl ether to give the title compound as a solid (yield 12.1 mg, 33%) .
1H-NMR (DMSO-d6)5: 1.80 (3H, s) , 2.06 (3H, s) , 2.58 (3H, s) , 2.62 (3H, s), 4.03 (2H, s), 7.05-7.07 (2H, m), 7.37-7.44 (3H,
m) , 7.67 (1H, s), 8.62 (2H, br).
Example 16 [5-(2-fluorophenyl)-4-methyl-l-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine hydrochloride
To a solution of 5-(2-fluorophenyl)-4-methyl-l-(pyridin30 3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde (382 mg) in methanol (5 mL) and tetrahydrofuran (2 mL) was added a 40% methylamine methanol solution (1.1 mL), and the mixture was stirred at room temperature for 4 hr. Sodium borohydride (51 mg) was added to the reaction mixture, and the mixture was further stirred for 15 min. The reaction mixture was concentrated
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2015268744 15 Dec 2015 under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate) to give a free salt of the title compound (yield 342 mg) . To a solution of the io obtained free salt (336 mg) in ethanol (5 mL) was added a 4 mol/L hydrogen chloride-ethyl acetate solution (5.0 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title .
compound as white crystals (yield 197 mg, 46%).
•’’H-NMR (DMSO-d6)5: 1-76 (3H, s) , 2.59 (3H, t, J=5.4 Hz), 4.01 (2H, t, J=5.4 Hz), 7.03-7.08 (1H, m), 7.21-7.28 (2H, m), 7.517.64 (2H, m), 7.82-7.86 (2H, m), 8.53 (1H, d, J=2.4 Hz), 8.808.89 (3H, m).
Example 17
1-[1-(2-chloropyridin-3-ylsulfonyl)-5-phenyl-lH-pyrrol-3-yl]N-methylmethanamine hydrochloride
To a solution (3 mL) of tert-butyl {[1-(2-chloro-3pyridinesulfonyl)-5-phenyl-lH-pyrrol-325 yl]methyl}methylcarbamate (70 mg) in ethyl acetate was added a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to give the title compound (yield 29 mg, 49%).
1H-NMR (DMSO-d6)g: 2.56 (3H, s) , 4.04 (2H, s) , 6.48 (1H, s) , 6.99-7.02 (2H, m) , 7.25-7.36 (4H, m) , 7.66-7.69 (1H, m) , 7.83 (1H, s), 8.60-8.62 (1H, m) , 8.79 (2H, br) .
Example 18
5-({4-[(methylamino) methyl]-2-phenyl-lH-pyrrol-l169
2015268744 15 Dec 2015 yl}sulfonyl)pyrimi dine-2-amine
To a solution (4 mL) of 1-(2-chloropyrimidin-5ylsulfonyl)-5-phenyl-lH-pyrrole-3-carbaldehyde (139 mg) in tetrahydrofuran was added a 0.5 mol/L ammonia-dioxane solution (4 mL) . After stirring at room temperature for 1 hr, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
io The residue was dissolved in a tetrahydrofuran (5 mL), a 2 mol/L solution (0.75 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred overnight at room temperature. The reaction mixture was added to a solution (2 mLj of sodium borohydride (38 mg) in methanol, and the mixture was stirred at room temperature for 5 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by HPLC (ODS, 0.1% trifluoroacetic acid-containing water-0.1% trifluoroacetic acid-containing acetonitrile=9:l_»0.1% trifluoroacetic acid-containing acetonitrile) to give trifluoroacetate of the title compound. The obtained trifluoroacetate was neutralized with a saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and crystallized crystals were washed with diisopropyl ether to give the title compound as a colorless solid (yield 23 mg, 17%).
1H-NMR (DMSO-d6)5·. 2.27 (3H, s) , 3.52 (2H, s) , 6.31 (1H, s) , 7.26-7.40 (6H, m), 7.94 (2H, br), 8.00 (2H, s), 1H not detected.
Example 19
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1- [ (imidazo[1,2-a]pyrimidin-6-ylsulfonyl)-5-phenyl-lH-pyrrol3-yl]-N-methylmethanamine dihydrochloride
Under a nitrogen atmosphere, a solution of ethyl 1(imidazo[1,2-a]pyrimidin-6-ylsulfonyl)-5-phenyl-lH-pyrrole-35 carboxylate (242 mg) in tetrahydrofuran (10 mL) was cooled to -78°C, a 1.5 mol/L solution (2.0 mL) of diisobutylaluminum hydride in toluene was added with stirring. After stirring at the same temperature for 1 hr, the mixture was warmed to -20°C over 1 hr. Water (30 mL) was added and, after stirring at the io same temperature for 5 min, the mixture was allowed to warm to 0°C over 10 min. Ethyl acetate (20 mL) was added and, after stirring at the same temperature for 15 min, the mixture was stirred at room temperature for 20 min. The reaction mixture in a gel state was filtered through celite, and celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 mL), manganese dioxide (75% chemically treated product, 2.0 g) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, the residue was dissolved in absolute tetrahydrofuran (5 mL), a 2 mol/L solution (0.6 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was added to a solution of sodium borohydride (45 mg) in methanol (2 mL), and the mixture was stirred at the same temperature for 20 min. The reaction mixture was diluted with
3o ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), di-tert-butyl bicarbonate (0.22 g), sodium hydrogencarbonate (84 mg) and water (5 mL) were added, and the mixture was stirred at room temperature for 30 min.
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The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), manganese dioxide (75% chemically treated product, 1.0 g) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel io column chromatography (eluent: hexane-ethyl acetate=19:l-»0:l) to give an oil. The obtained oil was dissolved in ethanol (1 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 2 hr, the solvent was evaporated under reduced pressure, and the is residue was triturated with ethyl acetate-ethanol to give the title compound as a brown solid (yield 8.5 mg, 3%).
1H-NMR (DMSO-d6)5: 2.50 (3H, s) , 4.02-4.05 (2H, m) , 6.49 (1H, s), 7.16-7.19 (2H, m) , 7.32-7.44 (3H, m), 7.79 (1H, s), 7.927.99 (2H, m), 8.29-8.30 (1H, m) , 8.97 (2H, br), 9.23-9.24 (1H,
m), 1H not detected.
Example 20
N-methyl-1-[5-phenyl-l-(pyridazin-3-ylsulfonyl)-lH-pyrrol-3yl]methanamine fumarate
Under a nitrogen atmosphere, a solution of ethyl 525 phenyl-1-(pyridazin-3-ylsulfonyl)-lH-pyrrole-3-carboxylate (567 mg) in tetrahydrofuran (16 mL) was cooled to -78°C, a 1.5 mol/L solution (6,4 mL) of diisobutylaluminum hydride in toluene was added with stirring. The reaction mixture warmed to -20°C over 1 hr. Water (75 mL) was added, and after stirring at the same temperature for 5 min, the mixture was allowed to warm to 0°C over 10 min. Ethyl acetate (75 mL) was added, and after stirring at the same temperature for 15 min, the.mixture was stirred at room temperature for 20 min. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The organic layer was separated 172
2015268744 15 Dec 2015 from the filtrate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), manganese dioxide (75% chemically treated product, 5.0 g) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was dissolved in absolute tetrahydrofuran (15 mL). A 2 mol/L io solution (1.5 mL) of methylamine -in tetrahydro furan was added, and the mixture was stirred overnight at room temperature. The reaction mixture was added to a solution of sodium borohydride (66 mg) in methanol (5 mL), and the mixture was stirred at the same temperature for 20 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by HPLC (ODS, 0.1% trifluoroacetic acid-containing water-0.1% trifluoroacetic acid-containing acetonitrile=9:1—>0.1% trifluoroacetic acidcontaining acetonitrile) to give trifluoroacetate of the title compound. The obtained trifluoroacetate was neutralized with a saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a free salt (59 mg) of the title compound. The obtained free salt (59 mg) was dissolved in methanol (2 mL) and ethyl acetate (2 mL), and fumaric acid (21 mg) was added. The solvent was evaporated under reduced pressure, and recrystallization from ethyl acetate-methanol gave the title compound as a pale-yellow solid (yield 41 mg, 6%).
1H-NMR (DMSO-ds)5: 2.42 (3H, s) , 3.82 (2H, s) , 6.41 (1H, s) ,
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6.47 (2H, s), 7.09-7.12 (2H, m), 7.29-7.38 (3H, m), 7.63 (1H, S), 7.80-7.83 (1H, m) , 7.91-7.96 (1H, m) , 9.48-9.50 (1H, m) ,
3H not detected.
Example 21 s N-methyl-1-[1-(5-methyl-3-pyridinesulfonyl)-5-phenyl-lHpyrrol-3-yl]methanamine fumarate
To a solution (5 mL) of tert-butyl {[1-(6-chloro-5methyl-3-pyridinesulfonyl)-5-phenyl-lH-pyrrol-3yl]methylJmethylcarbamate (237 mg) in tetrahydrofuran was io added hydrazine (160 mg) at room temperature with stirring. After stirring at the same temperature for 3 hr, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was dissolved in tetrahydrofuran (30 mL), manganese dioxide (75% chemically treated product, 1.0 g) was added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexaneethyl acetate=19:1-»1:1) to give an oil. The obtained oil was dissolved in ethanol (2 mL), and a 4 mol/L hydrogen chloride25 ethyl acetate solution (1 mL) was added. After stirring at room temperature for 2 hr, the solvent was evaporated under reduced pressure, a saturated aqueous'sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue (93 mg) was dissolved in ethanol (3 mL), and fumaric acid (29 mg) was added. After allowing to stand at room temperature for 30 min, the precipitated crystals were collected by filtration and washed with methanol to give the title compound as a colorless 174
2015268744 15 Dec 2015
solid (yield 91 mg, 40%) .
XH-NMR (DMSO-d6)5: 2.27 (3H, s), 2.38 (3H, s), 3.75 (2H, s),
6.37 (1H, s), 6.47 (2H, s) , 7.15-7.17 (2H, m), 7.36-7.45 (4H,
m), 7.58 (1H, s), 8.28 (1H, s), 8.68 (1H,s), 3H not detected
Example 22
5-({4-[(methylamino)methyl]-2-phenyl-lH-pyrrol-lyl}sulfonyl)pyridin-2-ol hydrochloride tert-Butyl {[1-(6-chloro-3-pyridinesulfonyl)-5-phenyl-lHpyrrol-3-yl]methyl}methylcarbamate (175 mg) was dissolved in io tetrahydrofuran (10 mL), a 8 mol/L aqueous sodium hydroxide solution (3.8 mL) was added, and the mixture was stirred at ' 50°C for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=l9: l-»0:1) to give a free salt of the title compound. To a solution (1 mL) of the obtained free salt in ethanol was added a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) . After stirring at room temperature for 4 hr, the solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to give the title compound (yield 40 mg, 27%).
XH-NMR (DMSO-d6)5: 2.50 (3H, s) , 3.97-4.01 (2H, m) , 6.32-6.36 (1H, m), 6.47 (1H, s), 7.20-7.23 (4H, m) , 7.37-7.48 (3H, m) ,
7.66 (1H, s), 8.94 (2H, br), 12.35 (1H, br).
Example 23
5-({4-[(methylamino)methyl]-2-phenyl-lH-pyrrol-lyl}sulfonyl)pyridine-2-carbonitrile hydrochloride
Under an argon atmosphere, a mixture of tert-butyl { [1(6-chloro-3-pyridinesulfonyl) -5-phenyl-lH-pyrrol-3yl]methyl}methylcarbamate (100 mg), zinc (II) cyanide (51 mg), tetrakis(triphenylphosphine)palladium (50 mg) and N,Ndimethylformamide (4 mL) was stirred at 100°C for 2 hr. The reaction mixture was diluted with ethyl acetate, washed 175
2015268744 15 Dec 2015 successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:l-»7 :3) to give an oil. The obtained oil was dissolved in ethyl acetate (2 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 1 hr, the solvent was evaporated under reduced pressure, io and the residue was crystallized from ethanol to give the title compound (yield 57 mg, 68%) .
’'H-NMR (DMSO-d6)5: 2.50 (3H, s) , 3.98 (2H, s) , 6.52 (1H, s) , 7.15-7.17 (2H, m) , 7.37-7.47 (3H, m), 7.79 (1H, s), 8.04-8.07 (1H, m), 8.22-8.24 (1H, m) , 8.61-8.62 (1H, m), 9.03 (2H, br).
Example 24
N-methyl-1-{1-[(6-methylpyridin-3-yl)sulfonyl]-5-phenyl-1Hpyrrol-3-yljmethanamine dihydrochloride tert-Butyl ({[1- (6-methylpyridin-3-yl)sulfonyl]-5-phenyl lH-pyrrol-3-ylJmethyl)methylcarbamate (113 mg) was dissolved in ethanol (2 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 40 mg, 38%).
1H-NMR (DMSO-ds)5: 2.50-2.53 (6H, m) , 3.97-3.99 (2H, m) , 6.46 (1H, s), 7.16-7.18 (2H, m), 7.38-7.44 (4H, m), 7.65-7.75 (2H, m), 8.34 (1H, s), 8.98 (2H, br), 1H not detected.
Example 25
N-methyl-1-[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-IH-pyrrol30 3-yl]methanamine hydrochloride
By a similar operation as in Example 24 and using tertbutyl {[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-lH-pyrrol-3yljmethyljmethylcarbamate (182 mg), the title compound was obtained as colorless crystals (yield 64 mg, 41%).
1H-NMR (CDC13)5: 2.60 (3H, s), 3.98 (2H, brs), 6.57 (1H, brs),
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7.00 (1H, brd, J=4.5 Hz), 7.16 (1H, brs), 7.26-7.31 (2H, m), 7.70 (2H, brs), 8.61 (1H, brs), 8.73 (1H, brs), 9.86 (2H, brs) .
Example 26
1- [5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol-3yl]-N-methylmethanamine dihydrochloride tert-Butyl {[5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl) lH-pyrrol-3-yl]methyl}methylcarbamate (293 mg) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was io added at 0°C, and the mixture was stirred at room temperature for 3 hr. The reaction solution was basified by adding dropwise to a 6% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=l: 1-»1: 9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give the title compound as colorless crystals (yield 110 mg, 40%). 1H-NMR (DMSO-d6)5: 2.47-2.51 (3H, m) , 3.97 (2H, t, J=6.0 Hz),
6.52-6.53 (1H, m), 7.15-7.26 (4H, m), 7.57-7.61 (1H, m), 7.797.85 (2H, m), 8.00 (1H, d, J=2.4 Hz), 8.85-8.87 (1H, m), 9.22 (2H, br), 1H not detected.
Example 27
N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H30 pyrrol-3-yl]methanamine dihydrochloride
By a similar operation as in Example 26 and using tertbutyl methyl{[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]methyl}carbamate (210 mg), the title compound was obtained as colorless crystals (yield 67 mg, 34%) . More specifically, tert-butyl methyl{[5-(2-methylphenyl)-1177
2015268744 15 Dec 2015 (pyridin-3-ylsulfonyl) -lH-pyrrol-3-yl]methyl}carbamate (210 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added at 0°C, and the mixture was stirred at room temperature for 2 hr. The reaction solution was basified by adding dropwise to a 6% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column io chromatography (eluent: hexane-ethyl acetate=l: 1_»1:9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetateethanol to give the title compound as colorless crystals
(yield 67 mg, 34%) .
1 H-NMR (DMSO-d6)5: 1.80 (3H, s), 2.49-2.53 (3H, m), 4.00 (2H,
t, J=5.4 Hz), 6.46 (1H, d, J=2.4 Hz) , 6.83 (1H, d, J=7.8 Hz) ,
7.13-7.22 (2H, m), 7.33 -7.39 (1H, m), 7.59-7.63 (1H, m), 7.80-
7.85 (2H, m), 8.46 (1H, d, J=2.4 Hz), 8.88-8.90 (1H, m), 9.27
(2H, br), 1H not detected, melting point 196-200°C
Example 28
1-[5-(4-fluoro-2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine dihydrochloride
By a similar operation as in Example 26 and using tertbutyl {[5-(4-fluoro-2-methylphenyl)-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl]methyl}methylcarbamate (216 mg), the title compound was obtained as colorless crystals (yield 81 mg,
40%) .
“H-NMR (DMSO-d6)5: 1.80 (3H, s) , 2.49-2.51 (3H, m) , 4.00 (2H, t, J=6.0 Hz), 6.47 (1H, d, J=2.1 Hz), 6.85-6.90 (1H, m) , 6.987.12 (2H, m), 7.61-7.65 (1H, m), 7.81-7.88 (2H, m) , 8.51 (1H, d, J=2.7 Hz), 8.89-8.91 (1H, m) , 9.29 (2H, br), 1H not
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Example 29
N-methyl-1- [5- (4-methyl-3-thienyl) -1- (pyridin-3-ylsulfonyl) lH-pyrrol-3-yl]methanamine dihydrochloride
By a similar operation as in Example 26 and using tertbutyl methyl{[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl]methyl}carbamate (200 mg), the title compound was obtained as colorless crystals (yield 125 mg, 67%). More specifically, tert-butyl methyl{[5-(4-methyl-3-thienyl)-1lo (pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]methyl}carbamate ¢200 mg) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added at 0°C, and the mixture was stirred at room temperature for 1 hr. The reaction solution was basified by adding dropwise to a 6% aqueous sodium hydrogencarbonate is solution, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=l: 1—>1: 9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate25 ethanol to give the title compound as colorless crystals (yield 125 mg, 67%).
XH-NMR (DMSO-d6)5: 1.71 (3H, s) , 2.49-2.51 (3H, m) , 3.98 (2H, t, J=5.7 Hz), 6.49 (1H, d, J=2.1 Hz), 7.16-7.23 (2H, m) , 7.587.62 (1H, m), 7.79-7.86 (2H, m), 8.50-8.51 (1H, m), 8.87-8.89 (1H, m), 9.30 (2H, br), 1H not detected, melting point 178-181°C Example 30
3-[4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1Hpyrrole-2-yl]benzonitrile hydrochloride
By a similar operation as in Example 26 and using tert179
2015268744 15 Dec 2015 butyl {[5-(3-cyanophenyl)-1-(pyridin-3-ylsulfonyl)-IH-pyrrol3-yl]methyljmethylcarbamate (298 mg) , the title compound was obtained as colorless crystals (yield 132 mg, 52%).
1H-NMR (DMSO-d6)5: 2.48-2.51 (3H, m) , 3.98 (2H, brs), 6.65 (1H, d, J=1.8 Hz), 7.51-7.65 (4H, m) , 7.85-7.95 (3H, m), 8.55 (1H, d, J=2.4 Hz), 8.88-8.90 (1H, m), 9.25 (2H, br).
Example 31
1-[5-(2-chlorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol-3yl]-N-methylmethanamine dihydrochloride io By a similar operation as in Example 26 and using tertbutyl {[5-(2-chlorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]methyl}methylcarbamate (171 mg), the title compound was obtained as colorless crystals (yield 74 mg, 46%).
1H-NMR (DMSO-de)5: 2.50 (3H, br) , 4.01 (2H, t, J=6.0 Hz), 5.40 (1H, br), 6.55 (1H, d, J=2.1 Hz), 7.13-7.16 (1H, m), 7.35-7.40 (1H, m), 7.47-7.51 (2H, m) , 7.61-7.65 (1H, m) , 7.84-7.93 (2H, m), 8.57 (1H, d, J=2.1 Hz), 8.89-8.91 (1H, m), 9.23 (2H, br). Example 32
1-[5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-IH-pyrrol2o 3-yl]-N-methylmethanamine dihydrochloride
By a similar operation as in Example 26 and using tertbutyl { [5-(2,4-difluorophenyl) -1- (pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]methyljmethylcarbamate (110 mg), the title compound was obtained as colorless crystals (yield 58 mg,
56%) .
XH-NMR (DMSO-d6)5: 2.48-2.51 (3H, m) , 3.98 (2H, t, J=5.7 Hz), 6.62 (1H, d, J=1.8 Hz), 7.13-7.17 (2H, m) , 7.28-7.36 (1H, m) , 7.62-7.66 (1H, m) , 7.86-7.95 (2H, m), 8.61 (1H, d, J=2.4 Hz), 8.89-8.91 (1H, m) , 9.31 (2H, br), 1H not detected.
Example 33
1-[5-(2, 5-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol3-ylj -N-methylmethanamine hydrochloride
By a similar operation as in Example 26 and using tertbutyl {[5-(2, 5-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H35 pyrrol-3-yl]methyljmethylcarbamate (105 mg), the title 180
2015268744 15 Dec 2015 compound was obtained as colorless crystals (yield 39 mg,
43%) .
1H-NMR (DMSO-d6)6: 2.50-2.51 (3H, m) , 3.99 (2H, brs), 6.62 (1H, d, J=1.8 Hz), 7.00-7.06 (1H, nt), 7.27-7.44 (2H, m), 7.63-7.67 (1H, m), 7.86 (1H, br), 7.94-7.97 (1H, m) , 8.65 (1H, d, J=2.7 Hz), 8.90-8.92 (1H, m), 9.08 (2H, m).
Example 34
1- [5-(4-chloro-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine dihydrochloride io By a similar operation as in Example 26 and using tertbutyl {[5-(4-chloro-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl]methyl}methylcarbamate (103 mg), the title compound was obtained as colorless crystals (yield 32 mg,
33%) .
1H-NMR (DMSO-d6)5: 2.47-2.52 (3H, m) , 3.97 (2H, t, J=6.0 Hz),
5.10 (1H, br), 6.64 (1H, brs), 7.15 (1H, t, J=7.8 Hz), 7.347.36 (1H, m), 7.50-7.53 (1H, m) , 7.62-7.67 (1H, m), 7.88 (1H, brs), 7.95-7.98 (1H, m), 8.64 (1H, d, J=2.4 Hz), 8.90 (1H, d,
J=4.8 Hz), 9.33 (2H, br).
Example 35
1-[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol-3yl]-N-methylmethanamine hydrochloride tert-Butyl {[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl) lH-pyrrol-3-yl]methyl}methylcarbamate (280 mg) was dissolved in ethyl acetate (3 ml), a 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction solution was basified by adding dropwise to a 6% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetatehexane=l:1_>9:1) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl 181
2015268744 15 Dec 2015 acetate, a 4 mol/L hydrogen chloride-ethyl acetate solution was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate and hexane, and recrystallized from ethyl acetate-ethanol to give the title compound as colorless crystals (yield 84 mg, 35%). 1H-NMR (DMSO-d6)5: 2.49-2.51 (3H, m) , 3.97 (2H, s) , 6.57 (1H, d, J=1.8 Hz), 6.98-7.02 (2H, m), 7.27-7.33 (1H, m), 7.40-7.47 (1H, m), 7.58-7.62 (1H, m) , 7.80-7.87 (2H, m), 8.54 (1H, d, J=2.7 Hz), 8.86-8.88 (1H, m), 9.06 (2H, br).
io Example 36
1-[5-(2-fluorophenyl)-2-methyl-l-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine fumarate
A suspension of tert-butyl {[5-bromo-2-methyl-l-(pyridin3-ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate (369 mg), (2-fluorophenyl)boronic acid (234 mg), sodium carbonate (265 mg) and tetrakis(triphenylphosphine)palladium (48.9 mg) in 1,2-dimethoxyethane (15 mL) and water ¢7.5 mL) was stirred at 105°C for 12 hr. The reaction mixture was allowed to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:
hexane-ethyl acetate=l: 4) to give an oil. The obtained oil was dissolved in ethanol (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized by adding a saturated aqueous sodium hydrogencarbonate solution (50 mL). The mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was 182
2015268744 15 Dec 2015 purified by basic silica gel column chromatography (eluent: ethyl acetate), and further by HPLC (ODS, 0.1% trifluoroacetic acid-containing water-0.1% trifluoroacetic acid-containing acetonitrile=9:l-»0.1% trifluoroacetic acid-containing acetonitrile) to give trifluoroacetate of the title compound. The obtained trifluoroacetate was neutralized with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate io solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a free salt of the title compound (yield 65 mg) . The free salt (62 mg) was dissolved in ethyl acetate (2 mL), a solution of fumaric acid (17 mg) in methanol (2 mL) was added, and the mixture was stirred for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as white crystals (yield 25 mg, 7%).
1H-NMR (DMSO-d6)5: 2.35 (3H, s) , 2.40 (3H, s) , 3.75 (2H, s) ,
6.46 (3H, s), 7.20-7.28 (3H, s), 7.44-7.52 (1H, m), 7.63-7.67 (1H, m), 7.88-7.92 (1H, m), 8.61 (1H, d, J=2.4 Hz), 8.88-8.90 (1H, m), 3H not detected.
Example 37
N-methyl-1-(5-phenyl-l-{[5-(trifluoromethyl)pyridin-325 yl]sulfonyl}-lH-pyrrol-3-yl)methanamine hydrochloride
To a solution of 5-phenyl-l-{[5-(trifluoromethyl)pyridin
3-yl]sulfonyl}-lH-pyrrole-3-carbaldehyde (137 mg) in absolute tetrahydrofuran (5 mL) was added at room temperature, a 2 mol/L solution (0.36 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred for 16 hr. Sodium borohydride (27 mg) and methanol (2 mL) were added, and the mixture was stirred at the same temperature for 2 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine,
183
2015268744 15 Dec 2015 dried over anhydrous magnesium, sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), di-tert-butyl bicarbonate (218 mg), water (2 mL) and sodium hydrogencarbonate (84 mg) were added, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran io (20 mL), manganese dioxide (75% chemically treated product,
1.0 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1—>1:1), fractions containing a material showing Rf value of 0.46 (eluent:hexane-ethyl acetate=3:l) by TLC analysis were collected and concentrated under reduced pressure. The residue was dissolved in ethanol (1 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 2 hr, the solvent was evaporated under reduced pressure. The residue was purified by HPLC (ODS, 0.1% trifluoroacetic acidcontaining .water-0 . 1% trifluoroacetic acid-containing acetonitrile=97:3->0.1% trifluoroacetic acid-containing acetonitrile) to give trifluoroacetate of the title compound. The obtained trifluoroacetate was neutralized with a saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. Recrystallization from ethanol gave 184
2015268744 15 Dec 2015 the title compound (yield 23 mg, 15%) .
1H-NMR (DMSO-d6)5: 2.50 (3H, s) , 3.97 (2H, s) , 6.49 (1H, s) , 7.13-7.15 (2H, m), 7.37-7.48 (3H, m), 7.80-7.87 (2H, m), 8.72 (2H, br), 8.86 (1H, s), 9.33 (1H, s).
Example 38
N-methyl-l-{l-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-lHpyrrol-3-ylJmethanamine dihydrochloride
By a similar reaction as in Example 12 and using 1—[(2— methylpyridin-3-yl)sulfonyl]-5-phenyl-lH-pyrrole-3lo carbaldehyde (180 mg), the title compound was obtained as a solid (yield 110 mg, 48%).
1H-NMR (DMSO-de)6: 2.37 (3H, s), 2.53-2.57 (3H, m) , 4.02-4.10 (2H, m) , 6.51 (1H, d, J=1.8 Hz), 7.01 (2H, d, J=6.9 Hz), 7.117.35 (4H, m), 7.44-7.46 (1H, m), 7.84 (1H, d, J=2.1 Hz), 8.6115 8.62 (1H, m), 9.07 (2H, br), 1H not detected.
Example 39
1-[5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl 3-N-methylmethanamine fumarate
5-(2, 6-Difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H20 pyrrole-3-carbaldehyde (250 mg)· was added to a mixture of a 40% methylamine methanol solution (560 mg) and methanol (5 mL) at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (41 mg) was added to the reaction mixture and the mixture was stirred for 10 min. The reaction mixture was concentrated under reduced pressure at 30°C. The residue was extracted with a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate), dissolved in ethanol (5 mL), and a solution of fumaric acid (84 mg) in ethanol (5 mL) was added to allow crystallization to give the title compound as colorless crystals (yield 229 mg, 67%).
1H-NMR (DMSO-d6)5: 2.43 (3H, s) , 3.85 (2H, s) , 6.48 (2H, s),
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6.57 (1H, d, J=1.7 Hz), 7.12-7.18 (2H, m) , 7.55-7.66 (2H, m) , 7.81 (1H, d, J=1.7 Hz), 7.93-7.97 (1H, m), 8.61 (1H, d, J=2.1 Hz), 8.90 (1H, dd, J=4.7, 1.5 Hz), 3H not detected.
Example 40
1-[5-(4-cyclohexylphenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]-N-methylmethanamine dihydrochloride
To a solution of 5-(4-cyclohexylphenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrole-3-carbaldehyde (0.78 g) in methanol (20 mL) were added methylammonium chloride (1.61 g) and sodium io cyanoborohydride (0.49 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=3:2->0:1) to give an oil (0.39 g) . The oil was dissolved in ethyl acetate (3 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1.5 mL) was added, and the mixture was concentrated under reduced pressure. Crystallization from methanol-ethyl acetate gave the title
compound as crystals (yield 0.41 g, 4 3%) .
1H-NMR (DMSO-d6)§: 1.20-1.46 (5H, m), 1.68-1.88 (5H, m) , 2.45-
2.59 (1H, m), 2.48 (3H, s), 3.97 (2H, d, J=5.3 Hz) , 6. 48 (1H,
s), 7.04 (2H, d, J=8.1 Hz), 7.20 (2H, d, J=8.1 Hz) , 7. 51-7.57
(1H, m), 7.73-7.79 (2H, m) , 8.43 (1H, s), 8.83 (1H, d, J=4.7
Hz), 9.17 (2H, s), 1H not detected.
Example 41
1-[4-fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]N-methylmethanamine dihydrochloride
By a similar reaction as in Example 12 and using 4fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carbaldehyde (121 mg), the title compound was obtained as a colorless solid (yield 30.7 mg, 20%) . More specifically, 4186
2015268744 15 Dec 2015 fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carbaldehyde (121 mg) was dissolved in tetrahydrofuran (5 mL), a 2 mol/L solution (0.22 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for
4 hr. A solution (2 mL) of sodium borohydride (28 mg) in methanol was added to the reaction mixture, and the mixture was stirred at room temperature for 20 min. A aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with io saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by.silica gel column chromatography (eluent: ethyl acetate-»ethyl acetate-methanol=l: 4) to give a free salt of the title compound. To a solution (2 mL) of the obtained free salt is in ethanol was added a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL). After allowing to stand at room temperature for 30 min, the mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a colorless solid (yield 30.7 mg,
20%) .
1H-NMR (DMSO-d6)5: 2.56-2.59 (3H, m) , 4.03-4.05 (2H, m) , 7.147.16 (2H, m), 7.41-7.48 (3H, m), 7.53-7.62 (1H, m), 7.80-7.85 (2H, m), 8.50 (1H, d, J=2.4 Hz), 8.88-8.89 (1H, m) , 9.07 (2H, br), 1H not detected.
melting point 201-203°C Example 42
1-[4-fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]N-me thylmethanamine
4-Fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-330 carbaldehyde (0.27 g) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution (0.8 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hr. Sodium borohydride (91 mg) and methanol (7 mL) were added, and the mixture was stirred at the same temperature for further 30 min. The reaction mixture was 187
2015268744 15 Dec 2015 concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane-ethyl acetate=19:l_>0:1) . The above-mentioned operation was repeated to give the title compound (0.22 g, yield 39%) as a colorless solid.
’’H-NMR (CDC13)6: 2.48 (3H, s) , 3.63 (2H, s) , 7.22-7.42 (7H, m) , io 7.56-7.60 (1H, m), 8.55 (1H, d, J=2.1 Hz), 8.73 (1H, dd,
J=4.8, 1.8 Hz), 1H not detected, melting point 98-99°C Example 43
1- [4-fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]15 N-methylmethanamine 0.5 fumarate
1-[4-Fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]-N-methylmethanamine (32 mg) was dissolved in ethanol (2 mL), fumaric acid (10 mg) was added, and the mixture was stood at room temperature for 1 hr. The precipitate was collected by filtration to give the title compound as a colorless solid (yield 16 mg, 42%).
1H-NMR (DMSO-d6)5: 2.30 (3H, s) , 3.60 (2H, S) , 6.50 (1H, s) , 7.18-7.21 (2H, m), 7.39-7.50 (4H, m), 7.57-7.61 (1H, m), 7.797.83 (1H, m), 8.50 (1H, d, J=2.1 Hz), 8.87 (1H, dd, J=5.1, 1.8
Hz), 2H not detected, melting point 163-166°C Example 44
1-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1Hpyrrol-3-yl}-N-methylmethanamine dihydrochloride
By a similar reaction as in Example 12 and using 5-(2fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]~lH-pyrrole-3carbaldehyde (134 mg), the title compound was obtained as a colorless solid (yield 96.1 mg, 57%). More specifically, 5-(2fluorophenyl)-1-[(6-methylpyridin-3-yl) sulfonyl]-lH-pyrrole-335 carbaldehyde (134 mg) was dissolved in tetrahydrofuran (10 188
2015268744 15 Dec 2015 mL), a 2 mol/L solution (0.6 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 4 hr. A solution (5 mL) of sodium borohydride (76 mg) in methanol was added to the reaction mixture, and the mixture was stirred at room temperature for 20 min. An aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified io by silica gel column chromatography (eluent: ethyl acetate-»ethyl acetate-methanol=l:4) to give a free salt of the title compound. To a solution (2 mL) of the obtained free salt in ethanol was added a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL). After allowing to stand at room temperature for 30 min, the mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a colorless solid (yield 96.1 mg, 57%) .
^i-NMR (DMSO-d6)5: 2.50-2.56 (6H, m) , 3.97-4.02 (2H, m) , 6.55 (1H, d, J=1.8 Hz), 7.08-7.11 (1H, m), 7.22-7.26 (2H, m), 7.477.60 (2H, m), 7.76-7.82 (2H, m), 8.44 (1H, d, J=2.4 Hz), 9.04 (2H, br), 1H not detected.
melting point 212~213°C Example 45
1-[5-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-lH-pyrrol-3yl]-N-methylmethanamine hydrochloride
By a similar reaction as in Example 12 and using 5-(2fluorophenyl)-1-(pyridin-2-ylsulfonyl)-lH-pyrrole-3carbaldehyde (183 mg), the title compound was obtained as a colorless solid (yield 78.3 mg, 37%).
1H-NMR (DMSO-d6)5: 2.54 (3H, s) , 4.02 (2H, s) , 6:52 (1H, d, J=2.1 Hz), 7.00-7.04 (1H, m) , 7.11-7.19 (2H, m) , 7.46-7.51 (1H, m), 7.57-7.60 (1H, m) , 7.74-7.78 (2H, m), 8.03-8.08 (1H, m), 8.70-8.85 (3H, m).
Example 46
189
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1-{5-(2-fluorophenyl)-1-[(l-methyl-lH-pyrazol-4-yl)sulfonyl]lH-pyrrol-3-yl[-N-methylmethanamine fumarate
To a solution (3 mL) of 5-(2-fluorophenyl)-1-[(1-methyllH-pyrazol-4-yl)sulfonyl]-lH-pyrrole-3-carbaldehyde (217 mg) in tetrahydrofuran were added a 40% methylamine methanol solution (152 mg) and methanol (1 mL) at room temperature.
After stirring at room temperature for 1 hr, sodium borohydride (82 mg) was added at 0°C. After stirring at room temperature for 30 min, water was added and the mixture was io extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexaneethyl acetate=l: 1—>1:9) to give a free salt of the title compound as a pale-yellow oil (yield 152 mg) . A solution of the obtained free salt in ethyl acetate (5 mL) was added to a solution of fumaric acid (50.6 mg) in methanol (1 mL), and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol/water=95/5 to give the title compound as colorless crystals (yield 143 mg, 48%).
H-NMR (DMSO-d6)6: 2.46 (3H, s), 3.82 (3H, s) , 3.85 (2H, s) ,
6.41 (1H, d, J=1.8 Hz), 6.46 (2H, s), 7.15-7.26 (3H, m) , 7.467.56 (3H, m), 8.11 (1H, s), 3H not detected.
Example 47
N-methyl-l-'[5- (2-methylphenyl) -1- (pyridin-3-ylsulfonyl) -1Hpyrrol-3-yl]methanamine fumarate
To a solution of 5-(2-methylphenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrole-3-carbaldehyde (521 mg) in . tetrahydrofuran (5 mL) and methanol (5 mL) was added a 40% methylamine methanol solution (373 mg) . After stirring at room temperature for 1 hr, sodium borohydride (202 mg) was added. After stirring at the same temperature for 30 min, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The
190
2015268744 15 Dec 2015 residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=l:1—>1:9) to give a free salt of the title compound as a yellow oil (yield 422 mg) . A solution of the obtained free salt in ethanol (5 mL) was added to a solution (15 mL) of fumaric acid (144 mg) in ethanol, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 414 mg, 56%).
1H-NMR (DMSO-d6)5: 1.81 (3H, s) , 2.45 (3H, s) , 3.88 (2H, s) ,
10 6,33 (1H, d, J=1.8 Hz) , 6.46 (2H, s), 6.83-6.85 (1H, m) , 7.12·
7.22 (2H, m) , 7.32-7.37 (1H, m), 7.57-7.61 (1H, m) , 7.69 (1H,
d, J= =1.8 Hz) , 7.78-7.82 (1H, m), 8.44-8.45 (1H, m) , 8.87- -8.89
(1H, m) , 3H not detected
melting point 207-210°C
Example 48
1-[4-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine fumarate
To a solution of 4-chloro-5-(2-fluorophenyl)-1-(pyridin3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde (429 mg) in tetrahydrofuran (5 mL) and methanol (3 mL) was added a 40% methylamine methanol solution (275 mg) at room temperature. After stirring for 30 min, sodium borohydride (99 mg) was added. After stirring at the same temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=l: 1-»1: 9) to give a free salt of the title compound as a yellow oil (yield 257 mg) . A solution of the obtained free salt in ethyl acetate (5 mL) was added to a solution (10 mL) of fumaric acid (79 mg) in methanol, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 216 mg, 36%).
’‘H-NMR (DMSO-d6)5: 2.43 (3H, s), 3.75 (2H, s) , 6.54 (2H, s) ,
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2015268744 15 Dec 2015
7.13-7.19 (1H, m), 7.24-7.32 (2H, m), 7.55-7.66 (2H, m) , 7.81 (1H, s), 7.88-7.92 (1H, m) , 8.56-8.57 (1H, m) , 8.90-8.92 (1H, m), 3H not detected.
Example 49
1- [4-fluoro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine fumarate
To a solution of 4-fluoro-5-(2-fluorophenyl)-1-(pyridin3-ylsulfonyl)pyrrole-3-carbaldehyde ¢0.60 g) in tetrahydrofuran (6 mL) and methanol (6 mL) was added a 40% io methylamine methanol solution (1.8 mL) and the mixture was stirred at room temperature for 30 min. Sodium borohydride (84 mg) was added at room temperature and the mixture was stirred for 5 min and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate) to give a free salt of the title compound as a pale-yellow oil (yield 0.36 g). The obtained free salt (0.36 g) was dissolved in ethanol (10 mL), and a solution of fumaric acid (0.12 g) in ethanol (10 mL) was added at room temperature. The reaction mixture was stirred for 14 hr, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 0.73 g, 43%).
1H-NMR (DMSO-d6)5: 2.36 (3H, s) , 3.69 (2H, s) , 6.54 (2H, s) , 7.21-7.32 (3H, m), 7.54-7.65 (3H, m), 7.86-7.90 (1H, m), 8.57 (1H, d, J=2.4 Hz), 8.89-8.91 (1H, m), 3H not detected.
Example 50
1-[4-fluoro-5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine fumarate
To a solution (5 mL) of 4-fluoro-5-(2-methylphenyl)-135 (pyridin-3-ylsulfonyl)pyrrole-3-carbaldehyde (0.45 g) in 192
2015268744 15 Dec 2015 tetrahydrofuran were added a 40% methylamine methanol solution (1.5 mL) and methanol (5 mL) and the mixture was stirred at room temperature for 30 min. Sodium borohydride (76 mg) was added at room temperature and the mixture was stirred for 30 min and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried io over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate) to give a free salt of the title compound as a pale-yellow oil (yield 0.33 g). The obtained free salt (0.33 g) was dissolved in ethanol (4 mL), and a solution of fumaric acid (0.10 g) in ethanol (10 mL) was added at room temperature. After stirring for 30 min, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 0.32 g, 54%).
1H-NMR (DMSO-d6)5: 1.76 (3H, s) , 2.43 (3H, s) , 3.80 (2H, s) ,
6.52 (2H, s), 6.97-6.99 (1H, m), 7.19-7.26 (2H, m), 7.37-7.42 (1H, m), 7.58-7.65 (2H, m) , 7.80-7.84 (1H, m), 7.46 (1H, d, J=2.4 Hz), 8.89-8.91 (1H, m), 3H not detected.
Example 51
1-[2-chloro-5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl]-N-methylmethanamine fumarate
2-chloro-5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl) lH-pyrrole-3-carbaldehyde (160 mg) was added to a mixture of 40% methylamine methanol solution (325 mg) and methanol (20 mL) at room temperature. After stirring for 30 min, sodium borohydride (48 mg) was added and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure at 30°C. The residue was extracted with a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate.
The extract was washed with saturated brine, dried over
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2015268744 15 Dec 2015 anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=l:0_»7:3) and dissolved in ethanol (2 mL), and a solution of fumaric acid (48 mg) in ethanol (2 mL) was added. Crystallization from the mixture gave the title compound as colorless crystals (yield 29 mg, 14%).
1H-NMR (DMSO-d6)5: 2.28 (3H, s) , 3.65 (2H, s) , 6.51 (2H, s) ,
6.73 (1H, s), 7.21-7.28 (2H, m), 7.55-7.65 (1H, m), 7.73-7.77 (1H, m), 8.08-8.12 (1H, m), 8.82 (1H, d, J=2.4 Hz), 8.96 (1H, dd, J=4.9, 1.5 Hz), 3H not detected.
Example 52
1-[2-chloro-5- (2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine fumarate
To a solution of methylamine hydrochloride (232 mg) in methanol (10 mL) was added 2-chloro-5-(2-fluorophenyl)-1(pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde (250 mg) and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (218 mg) was added and the mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure at 30°C and extracted with a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=l:0_»17 :3) and dissolved in ethyl acetate (10 mL), and a solution of fumaric acid (80 mg) in methanol (2 mL) was added. Crystallization from the mixture gave the title compound as colorless crystals (yield 97 mg,
29%) .
’H-NMR (DMSO-ds)6: 2.23 (3H, s) , 3.61 (2H, s) , 6.51 (2H, s) ,
6.61 (1H, s), 7.27-7.33 (2H, m), 7.43-7.56 (2H, m), 7.69-7.74 (1H, m) , 8.02-8.06 (1H, m), 8.80 (1H, brs), 8.94 (1H, dd,
J=4.8, 1.4 Hz), 3H not detected.
Example 53
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1—{1— [(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-lH-pyrrol-3-yl}N-methylmethanamine hydrochloride tert-Butyl ({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyllH-pyrrol-3-yl}methyl)methylcarbamate (120 mg) was dissolved in ethanol (3 mL), and a 4 mol/L hydrogen chlorideethyl acetate solution (1 mL) was added. After stirring at room temperature for 4 hr, the mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a solid (yield 51.3 mg, io 49%) .
XH-NMR (DMSO-d6)5: 2.50 (3H, s) , 3.96 (2H, m) , 6.51 (1H, s), 7.15-7.17 (2H, m) , 7.39-7.50 (3H, m) , 7.77 (1H, s) , 7.84 (1H, s) , 8.48 (1H, s), 8.89 (2H, br) , 9.03 (1H, s) .
Example 54
5- ({4- [ (methylamino)methyl] -2-phenyl-lH-pyrrol-1yl}sulfonyl)nicotinonitrile hydrochloride
A mixture of tert-butyl ({1-[(5-bromopyridin-3yl)sulfonyl]-5-phenyl~lH-pyrrol-3-yl}methyl)methylcarbamate (112 mg), zinc cyanide (50 mg) and N,N-dimethylformamide (4 mL) was degassed with argon gas.
Tetrakis(triphenylphosphine)palladium (46 mg) was added, and the mixture was stirred at 100°C for 1.5 hr. After cooling the reaction mixture to room temperature, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1_>3:2) to give a colorless oil. The obtained oil was dissolved in ethanol (2 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 1 hr, the mixture was concentrated under reduced pressure, and recrystallized from ethanol to give the title compound as a solid (yield 32.7 mg,
42%) .
195
2015268744 19 Feb 2016 1H-NMR (DMSO-d6)5·· 2.50-2.52 (3H, m) , 3.98 (2H, s) , 6.50 (1H, s), 7.13-7.16 (2H, m) , 7.37-7.50 (3H, m) , 7.76 (1H, d, J=1.8 Hz), 8.28 (1H, d, J=2.1 Hz), 8.66 (1H, d, J=2.4 Hz), 8.82 (2H, br), 9.31 (1H, d, J=2.1 Hz).
Example 55 methyl 5-({4-[(methylamino) methyl]-2-phenyl-lH-pyrrol-lyl}sulfonyl)nicotinate hydrochloride
A mixture of tert-butyl ({1-[(5-bromopyridin-3yl)sulfonyl]-5-phenyl-lH-pyrrol-310 yl jmethyl) methylcarbamate (112 mg), dichloro[bis(triphenylphosphine)]palladium (28 mg), triethylamine (0.25 mL) and methanol (15 mL) was stirred under a carbon monoxide atmosphere (3 atm) at 100°C for 12 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19: l->3:2) to give a colorless oil. The obtained oil was dissolved in ethanol (2 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 1 hr, the mixture was concentrated under reduced pressure, and recrystallized from ethanol to give the title compound as a solid (yield 47.0 mg, 56%).
1H-NMR (DMSO-d6)5: 2.49-2.51 (3H, m) , 3.91 (3H, s) , 3.98 (2H, s), 6.50 (1H, d, J=1.8 Hz), 7.15-7.17 (2H, m) , 7.37-7.50 (3H,
m), 7.80 (1H, s), 7.93-7.94 (1H, m), 8.81 (1H, d, J=2.1 Hz), 8.91 (2H, br), 9.29 (1H, d, J=2.1 Hz).
Example 56
N-methyl-1-{1-[(5-methylpyridin-3-yl)sulfonyl]-5-phenyl-lHpyrrol-3-yl}methanamine dihydrochloride
Under an argon atmosphere, a mixture of tert-butyl ({1196
2015268744 19 Feb 2016 [(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3 yl}methyl)methylcarbamate (112 mg), methylboronic acid (18 mg), tetrakis(triphenylphosphine)palladium (23 mg), potassium carbonate (138 mg) and 1,4-dioxane (5 mL) was stirred at 80°C for one day. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified io by silica gel column chromatography (eluent: hexane-ethyl acetate=19:l—>1:1) to give an oil. The oil was- dissolved in ethanol (1 mL), and a 4 mol/L hydrogen.chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 1 hr, the mixture was concentrated under reduced pressure.
The residue was recrystallized from ethanol-ethyl acetate to give the title compound as a colorless solid (yield 32.6 mg, 39%) .
“H-NMR (DMSO-ds)5: 2.28 (3H, s) , 2.50-2.53 (3H, m) , 3.94-4.00 (2H, m), '6.48 (1H, d, J=1.8 Hz), 7.12-7.15 (2H, m) , 7.37-7.52 (4H, m), 7.75 (1H, s), 8.29 (1H, d, J=2.1 Hz), 8.70 (1H, d, 0=1.5 Hz), 9.08 (2H, br), 1H not detected.
Example 57
1-[5-(2,4-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol3-yl]-N-methylmethanamine hydrochloride
By a similar operation as in Example 33 and using tertbutyl {[5-(2,4-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]methyl}methylcarbamate (177 mg), the title compound was obtained as colorless crystals (yield 68 mg,
45%) .
^-NMR (DMSO-ds)5* 1.76 (3H, s) , 2.32 (3H, s) , 2.49 (3H, s) , 3.99 (2H, s) , 6.38 (1H, d, J=1.8 Hz), 6.71 (1H, d, J=8.1 Hz)·, 6.95-7.03 (2H, m), 7.59-7.63 (1H, m) , 7.77-7.85 (2H, m) , 8.48 (1H, d, J=2.7 Hz), 8.88-8.90 (1H, m), 9.07 (2H, br).
Example 58
N-methyl-1-{5-[4-(methylsulfonyl) phenyl]-1-(pyridin-3197
2015268744 15 Dec 2015 ylsulfonyl)-lH-pyrrol-3-yl}methanamine dihydrochloride To a solution of tert-butyl methyl{[5-[4(methylsulfonyl)phenyl]-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-3yl]methyl}carbamate (275 mg) in ethyl acetate (2 mL) was added a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 4 hr. The precipitated crystals were collected by filtration, washed with ethyl acetate and recrystallized from ethanol to give the title compound as white crystals (yield 157 mg, 33%).
XH-NMR (DMSO-d6)5: 2.50 (3H, s) , 3.29 (3H, s) , 3.98 (2H, t,
J=5.6 Hz), 6.67 (1H, d, J=1.9 Hz), 7.48 (2H, d, J=8.7 Hz),
7.60 (1H, dd, J=8.6, 4.4 Hz), 7.86-7.97 (4H, m), 8.59 (1H, d, J=1.9 Hz), 8.88 (1H, dd, J=4.8, 1.4 Hz), 9.20 (2H, s), 1H not detected.
Example 59 (2-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1Hpyrrole-2-yl}phenyl)methanol fumarate tert-Butyl ({5-[2-(hydroxymethyl)phenyl]-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl}methyl)methylcarbamate (132 mg) was dissolved in trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was basified with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=l: 0->9:1) to give a free salt of the title compound as a colorless oil (yield 60.3 mg) . A solution of the obtained free salt in ethyl acetate (5 mL) was added to a solution of fumaric acid (19.6 mg) in methanol (2 mL), and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 48 mg, 35%) .
1H-NMR (DMSO-d6)5·. 2.42 (3H, S) , 3.83 (2H, s) , 4.00 (2H, s) ,
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6.35 (1H, d, J=1.5 Hz), 6.46 (2H, s) , 6.81-6.83 (1H, m), 7.177.22 (1H, m), 7,41-7.50 (2H, m), 7.55-7.60 (1H, m), 7.65 (1H, s), 7.75-7.78 (1H, m) , 8.46 (1H, d, J=2.4 Hz), 8.86 (1H, d,
J=4.8 Hz), 4H not detected.
Example 60
N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yljmethanamine fumarate
By a similar reaction as in Example 59 and using tertbutyl {[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1Hlo pyrrol-3-yl]methyl}methylcarbamate (943 mg), the title compound was obtained as colorless crystals (yield 553 mg,
57%). More specifically, tert-butyl {[5-(4-methyl-3-thienyl)1-(pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate (943 mg) was dissolved in trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was basified with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=l:9) to give a free salt of the title compound as a colorless oil (yield 631 mg) . A solution of the obtained free salt in ethyl acetate (5 mL) was added to a solution of fumaric acid (211 mg) in methanol (2 mL), and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol-water to give the title compound as colorless crystals (yield 553 mg, 57%) .
1H-NMR (DMSO-d6)5: 1.71 (3H, s), 2.42 (3H, s) , 3.83 (2H, s) ,
6.34 (1H, d, J=1.8 Hz), 6.45 (2H, s), 7.15-7.16 (1H, m), 7.217.22 (1H, m), 7.56-7.60 (1H, m), 7.64-7.65 (1H, m), 7.78-7.82 (1H, m), 8.48 (1H, d, J=2.4 Hz), 8.84-8.86 (1H, m), 3H not detected.
melting point 182-183°C
Example 61
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N-methyl-l-(5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-3yl) methanamine fumarate
5-Phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3carbaldehyde (650 mg) was dissolved in a mixture of a 40% methylamine methanol solution (808 mg) and methanol (30 mL) at room temperature and the mixture was stirred for 10 min.
Sodium borohydride (118 mg) was added and the mixture was stirred for 10 min. The reaction mixture was concentrated under reduced pressure at 30°C and the residue was extracted io with a saturated aqueous sodium hydrogencarbonate solution (40 mL) and ethyl acetate (80 mL) . The extract was washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography is (eluent: ethyl acetate) and a solution of fumaric acid (242 mg) in ethanol (24 mL) was added. The obtained crystals were collected by filtration and recrystallized from ethanol-water (85:15) to give the title compound as colorless crystals (yield 480 mg, 52%).
1H-NMR (DMSO-d6)5: 2.42 (3H, s) , 3.86 (2H, s) , 6.42 (1H, d,
J=1.9 Hz), 6.47 (2H, s), 7.14-7.18 (2H, m) , 7.34-7.46 (3H, m), 7.54-7.58 (1H, m) , 7.67 (1H, d, J=1.9 Hz), 7.76-7.80 (1H, m) , 8.46 (1H, dd, J=2.5, 0.8 Hz), 8.84 (1H, dd, J=4.9, 1.5 Hz), 3H not detected.
Example 62
1-[5-mesityl-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]-Nmethylmethanamine fumarate
To a solution of 5-mesityl-l-(pyridin-3-ylsulfonyl)-1Hpyrrole-3-carbaldehyde (0.37 g) in tetrahydrofuran (15 mL) was added dropwise a solution of a 40% methylamine methanol solution (0.41 g) in tetrahydrofuran (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Methanol (10 mL) was added, and the mixture was further stirred at room temperature for 2 hr. Sodium borohydride (0.06
g) was gradually added under ice-cooling, and the mixture was 200
2015268744 15 Dec 2015 stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=l: l-»ethyl acetate-methanol=5:1) to give a free salt of the title compound as a pale-brown oil.
io To a solution of the obtained free salt in ethyl acetate (5 mL) was added dropwise a solution of fumaric acid (0.14 g) in methanol (2.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 min. The precipitate was collected by filtration and recrystallized from ethanol-water to give the title compound as white crystals (yield 0.32 g,
61%) .
XH-NMR (DMSO-d6)5: 1.58 (6H, s) , 2.28 (3H, s) , 2.44 (3H, s) ,
3.87 (2H, s), 6.21 (1H, s), 6.45 (2H, s), 6.83 (2H, s), 7.60 (1H, dd, J=8.1, 1.8 Hz), 7.70 (1H, s) , 7.84 (1H, dd, J=8.4,
1.8Hz), 8.46 (1H, s), 8.88 (1H, d, J=3.9 Hz), 3H not detected.
Example 63
N-methyl-l-{5-[2-(methylthio)phenyl]-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl}methanamine fumarate
To a solution (3 mL) of 5-[2-(methylthio)phenyl]-1(pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde (170 mg) in tetrahydrofuran were added a 40% methylamine methanol solution (110 mg) and methanol (1 mL) at room temperature, and the mixture was stirred for 1 hr. Sodium borohydride (59.8 mg) was added under ice-cooling. After stirring at room temperature for 2 hr, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried.over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=l:1-»1: 9) 201
2015268744 15 Dec 2015 to give a free salt of the title compound as a colorless oil. The obtained free salt was dissolved in ethyl acetate, and added to a solution (1 mL) of fumaric acid (33.2 mg) in methanol. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 89.3 mg, 38%). fll-NMR (DMSO-ds)5·· 2.11 (3H, s) , 2.43 (3H, s) , 3.86 (2H, s) , 6.38 (1H, d, J=1.8 Hz), 6.46 (2H, s), 7.07-7.20 (3H, m) , 7.41
7.46 (1H, m), 7.53-7.58 (1H, m), 7.68 (1H, d, J=1.8 Hz), 7.79
7.83 (1H, m), 8.43 (1H, d, J=2.4 Hz), 8.82-8.84 (1H, m), 3H not detected.
Example 64
N-methyl-1-{5-[2-(methylsulfonyl)phenyl]-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-ylJmethanamine 0.5 fumarate
By a similar operation as in Example 63 and using 5—[2— (methylsulfonyl)phenyl]-1-(pyridin-3-ylsulfonyl)-lH-pyrrole-3 carbaldehyde (72.0 mg), the title compound was obtained as colorless crystals (yield 56.4 mg, 66%).
1H-NMR (DMSO-d6)5·· 2.37 (3H, s) , 3.00 (3H, s) , 3.71 (2H, s) ,
6.41 (1H, s), 6.48 (1H, d, J=1.5Hz), 7.14-7.17 (1H, m), 7.61 7.65 (2H, m), 7.70-7.80 (2H, m), 7.93-7.97 (1H, m) , 8.02-8.05 (1H, m), 8.66 (1H, d, J=2.1 Hz), 8.87-8.89 (1H, m), 2H not detected.
Example 65
2—{4—[(methylaminojmethyl]-1-(pyridin-3-ylsulfonyl)-1Hpyrrole-2-ylJbenzonitrile fumarate
By a similar operation as in Example 63 and using 2—[4— formyl-1-(pyridin-3-ylsulfonyl)-lH-pyrrole-2-yl]benzonitrile (129 mg), the title compound was obtained as colorless crystals (yield 69 mg, 38%).
1H-NMR (DMSO-d6)5: 2.39 (3H, s) , 3.82 (2H, s) , 6.47 (2H, s) , 6.58 (1H, d, J=1.8 Hz), 7.34-7.36 (1H, m), 7.59-7.76 (4H, m), 7.84-7.89 (2H, m), 8.53 (1H, d, J=2.4Hz), 8.87-8.89 (1H, m), 3H not detected.
Example 66
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1-[5-(2,6-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-IH-pyrrol3-yl] -N-methylmethanamine fumarate
To a solution of 5-(2,6-dimethylphenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrole-3-carbaldehyde (0.42 g) in tetrahydrofuran (15 mL) was added dropwise a solution of a 40% methylamine methanol solution (0.48 g) in tetrahydrofuran (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Methanol (10 mL) was added, and the mixture was further stirred at room temperature for 2 hr.
io Sodium borohydride (0.07 g) was gradually added under icecooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was is extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexaneethyl acetate=l:l-»ethyl acetate-methanol=5:1) to give a free salt of the title compound as a pale-brown oil. To a solution of the obtained free salt in ethyl acetate (5 mL) was added dropwise a solution of fumaric acid (0.12 g) in methanol (2 mL) under ice-cooling and the mixture was stirred at room temperature for 15 min. The precipitate was collected by filtration, and recrystallized from ethanol-water to give the title compound as white crystals (yield 0.18 g, 50%).
1H-NMR (DMSO-ds)5· 1.62 (6H, s)·, 2 .45 (3H, s) , 3. .88 (2H, s),
6.25 ( 1H, d, J=1.5 Hz) , 6.45 (2H, s) , 7.02 (2H, d, J=7.5 Hz),
7.24 ( 1H, d, J=7.5 HZ) , 7.58-7.62 (1H Z m), 7.71 (1H, s), 7.81-
30 7.85 ( 1H, m), 8.44 (1H, d, J=2.7 : Hz) , 8.89 (1H, dd, J=4.8, 1.5
Hz), 3H not detected.
Example 67
N-methyl-l-{5- [2-(methylsulfinyl)phenyl]-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-ylJmethanamine fumarate
To a suspension (5 mL) of sodium hydride (60% in oil, 203
2015268744 15 Dec 2015
39.5 mg) in tetrahydrofuran were added a solution (3 mL) of 5[2-(methylsulfinyl)phenyl]-lH-pyrrole-3-carbaldehyde (160 mg) in Ν,Ν-dimethylformamide, 15-crown-5 (181 mg), and pyridin-3ylsulfonyl chloride (134 mg) under ice-cooling. After stirring at room temperature for 1 hr, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in tetrahydrofuran (5 mL), a 40% methylamine methanol solution io (160 mg) was added at room temperature and the mixture was stirred for 1 hr. Sodium borohydride (86.5 mg) was added under ice-cooling. After stirring at room temperature for 2 hr, water was added and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=l:l-»ethyl acetate) to give a free salt of the title compound as a paleyellow oil. The obtained free salt was dissolved in ethyl acetate, and added to a solution (1 mL) of fumaric acid (28.1 mg) in methanol. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 83.9 mg, 24%) .
1H-NMR (DMSO-d6)5: 2.41 (3H, s) , 2.49-2.51 (3H, m) , 3.81 (2H, s), 6.46 (2H, s), 6.50 (1H, d, J=1.5 Hz), 7.00 (1H, br), 7.508.00 (6H, m), 8.57 (1H, br), 8.87-8.89 (1H, m), 3H not detected.
Example 68
2-(2-fluorophenyl)-4-[(methylamino)methyl]-1-(pyridin-3ylsulfonyl)-lH-pyrrole-3-carbonitrile fumarate
2-(2-Fluorophenyl)-4-formyl-l-(pyridin-3-ylsulfonyl)-1Hpyrrple-3-carbonitrile (295 mg) was dissolved in a solution of methylamine hydrochloride (1.12 g) in methanol (20 mL) and the mixture was stirred for 30 min. Sodium triacetoxyborohydride 204
2015268744 19 Feb 2016 (1.06 g) was added and the mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure at 30°C, a saturated aqueous sodium hydrogencarbonate solution (40 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL) . The extract was washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=85:15—>75:2 5) , and then by basic silica io gel column chromatography (eluent: ethyl acetate), and a solution of fumaric acid (96 mg) in ethanol (5 mL) was added. Crystallization from the mixture gave the title compound as colorless crystals (yield 120 mg, 30%) .
1H-NMR (DMSO-ds)5: 2.40 (3H, s) , 3.76 (2H, s) , 6.57 (2H, s),
7.28-7.37 (3H, m), 7.63-7.71 (2H, m), 7.87 (1H, s), 7.95-7.99 (1H, m), 8.64 (1H, dd, <>2.5, 0.6Hz), 8.94 (1H, dd, >4.9,
1.5 Hz), 3H not detected.
Example 59
5-(2-fluorophenyl)-3-[ (methylamino)methyl]-1-(pyridin-320 ylsulfonyl)-lH-pyrrole-2-carbonitrile fumarate
5-(2-Fluorophenyl)-3-formyl-l-(pyridin-3-ylsulfonyl)-1Hpyrrole-2-carbonitrile (650 mg) was dissolved in a mixture of a 40 methylamine methanol solution (808 mg) and methanol (30 rnL) at room temperature and the mixture was stirred for 10 min.
Sodium borohydride ¢118 mg) was added and the mixture was stirred for 10 min. The reaction mixture was concentrated under reduced pressure at 30°C, a saturated aqueous sodium hydrogencarbonate solution (40 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The extract was washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate) and a solution of fumaric acid (242 mg) in ethanol (24 mL) was added. The obtained crystals were collected by filtration, and 205
2015268744 15 Dec 2015 recrystallized from ethanol-water (85:15) to give the title compound as colorless crystals (yield 480 mg, 52%).
1H-NMR (DMSO-ds)5: 2.27 (3H, s) , 3.74 (2H, s) , 6.57 (2H, s) , 6.71 (1H, s), 7.29-7.38 (3H, m) , 7.58-7.64 (1H, m) , 7.71-7.75 (1H, m), 7.96-8.00 (1H, m), 8.66 (1H, d, J=2.3 Hz), 8.97 (1H, dd, J=4.9, 1.5 Hz), 3H not detected.
Example 70
4-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-lH-pyrrol2-yl}benzonitrile fumarate io To a solution (2 mL) of tert-butyl {[5-(4-cyanophenyl)-1 (pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]methyl]methylcarbamate (382 mg) in ethyl acetate was added a 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) at room temperature.
The mixture was stirred for 3 hr, and basified with a saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=l:1-»1:9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate, and added to a solution (2 mL) of fumaric acid (77.1 mg) in methanol. The solvent was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as colorless crystals (yield 218 mg, 55%) .
’’H-NMR (DMSO-d6)5: 2.37 (3H, s) , 3.79 (2H, s) , 6.47 (2H, s) ,
6.55 (1H, d, J=1.8 Hz), 7.40-7.44 (2H, m), 7.55-7.60 (1H, m) ,
7.70-7.71 (1H, m), 7.81-7.87 (3H, m) , 8.55-8.56 (1H, m), 8.848.86 (1H, m), 3H not detected.
Example 71
4-fluoro-3-{4-[(methylamino) methyl]-1-(pyridin-3-ylsulfonyl)lH-pyrrol-2-yl}benzonitrile 0.5 fumarate
By a similar operation as in Example 70 and using tert206
2015268744 15 Dec 2015 butyl {[5-(5-cyano-2-fluorophenyl)-1-(pyrldin-3-ylsulfonyl)lH-pyrrol-3-yl]methylJmethylcarbamate (100 mg), the title compound was obtained as colorless crystals (yield 37.1 mg,
40%) .
1H-N14R (DMSO-d6)5'. 2.34 (3H, s), 3.71 (2H, s), 6.44 (1H, s),
6.55 (1H, brs), 7.52 (1H, t, J=9.0 Hz), 7.60-7.68 (2H, m), 7.73-7.75 (1H, m), 7.91-7.93 (1H, m) , 8.03-8.08 (1H, m), 8.64 (1H, d, J=2.4 Hz), 8.88-8.90 (1H, m), 2H not detected.
Example 72 io 1-[5-(2-fluoro-5-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine fumarate tert-Butyl {[5-(2-fluoro-5-methoxyphenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methyl[methylcarbamate (475 mg) was dissolved in ethanol (10 mL), a 4 mol/L hydrogen chloride15 ethyl acetate solution (2 mL) was added and the mixture was stirred at 70°C for 30 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, added to a solution (13 mL) of fumaric acid (116 mg) in methanol, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 385 mg, 78%).
1H-NMR (DMSO-d6)5: 2.41 (3H, s) , 3.71 (3H, s) , 3.82 (2H, s) ,
6.47 (1H, d, J=1.9Hz), 6.48 (2H, s), 6.57-6.60 (1H, m), 7.027.07 (1H, m), 7.12-7.18 (1H, m), 7.60-7.64 (1H, m) , 7.70 (1H, d, J=1.5 Hz), 7.89-7.93 (1H, m), 8.60 (1H, d, J=2.3 Hz), 8.88 (1H, dd, J=4.9, 1.5 Hz), 3H not detected.
Example 73
1-(2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3ylsulfonyl)-lH-pyrrol-2-yl]phenyl)ethanone fumarate
By a similar operation as in Example 70 and using tert35 butyl {[5-(3-acetyl-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)207
2015268744 15 Dec 2015 lH-pyrrol-3-yl] methyl Jmethylcarbamate (118 mg), the title compound was obtained as colorless crystals (yield 44.7 mg, 37%) .
4l-NMR (DMSO-ds)5: 2.40 (3H, s) , 2.49-2.53 (3H, m) , 3.80 (2H,
m) , 6.47 (2H, s), 6.52 (1H, d, J=1.8 Hz), 7.32-7.40 (2H, m), 7.59-7.64 (1H, m), 7.73 (1H, d, J=1.8 Hz), 7.86-7.93 (2H, m), 8.60 (1H, d, J=2.7 Hz), 8.87-8.89 (1H, m), 3H not detected. Example 74
1-[5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H10 pyrrol-3-yl]-N-methylmethanamine fumarate
To a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1 (pyridin-3-ylsulfonyl) -lH-pyrrol-3-yl] methyl} methyl carbamate (2.48 g) in ethyl acetate (10 mL) and methanol (10 mL) was added a 4 mol/L hydrogen chloride-ethyl acetate solution (20 mL) at room temperature. After stirring for 5 hr, the mixture was concentrated under reduced pressure. The residue was basified with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=l: 1—>1: 9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (10 mL) and added to a solution of (10 mL) fumaric acid (350 mg) in methanol. The solvent was evaporated under reduced pressure and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as colorless crystals (yield 793 mg, 29%).
’’H-NMR (DMSO-ds)5: 2.39 (3H, s) , 3.78 (2H, s) , 6.48 (2H, s) ,
6.56 (1H, d, J=1.8 Hz), 7.40-7.44 (1H, m), 7.61-7.65 (1H, m) , 7.72-7.79 (2H, m) , 7.89-7.93 (1H, m) , 8.32-8.34 (1H, m), 8.62 (1H,. d, J=1.8 Hz), 8.88-8.90 (1H, m) , 3H not detected, melting point 183-184°C
Example 75
208
2015268744 15 Dec 2015
1-[5-(3-fluoropyridin-4-yl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine fumarate tert-Butyl {[5-(3-fluoropyridin-4-yl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate (60 mg) was dissolved in methanol (5 mL), a 4 mol/L hydrogen chlorideethyl acetate solution (1.5 mL) was added and the mixture was stirred at 70°C for 30 min. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium hydrogencarbonate solution was added. The mixture was io extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (8 mL), a solution of fumaric acid (58 mg) in methanol (2 mL) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 45 mg, 72%).
’H-NMR (DMSO-ds)5: 2.37 (3H, s) , 3.78 (2H, s) , 6.49 (2H, s) ,
6.64 (1H, d, J=1.5 Hz), 7.30-7.33 (1H, m), 7.62-7.66 (1H, m) ,
7.77 (1H, d, J=1.5 Hz), 7.94-7.98 (1H, m), 8.49-8.51 (1H, m) ,
8.64 (1H, d, J=1.5 Hz), 8.69 (1H, d, J=2.3 Hz), 8.90 (1H, dd,
J=4.9, 1.5 Hz), 3H not detected.
Example 76
1-[5-(2-chloropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine fumarate tert-Butyl {[5-(2-chloropyridin-3-yl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methylJmethylcarbamate (280 mg) was dissolved in ethanol (10 mL), a 4 mol/L hydrogen chlorideethyl acetate solution (2 mL) was added and the mixture was stirred at 70°C for 30 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL), a solution of fumaric acid (116 mg) in methanol (3 mL) was added, and the 209
2015268744 15 Dec 2015 obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 197 mg, 68%).
XH-NMR (DMSO-d5)6: 2.40 (3H, s) , 3.81 (2H, s) , 6.49 (2H, S) ,
6.52 (1H, d, J=1.9 Hz), 7.47-7.52 (1H, m) , 7.61-7.73 (3H, m) ,
7.90-7.94 (1H, m), 8.50 (1H, dd, J=4.9, 1.9 Hz), 8.63-8.64 (1H, m) , 8.90 (1H, dd, J=4.5, 1.5 Hz), 3H not detected.
Example 77
1-[5-(6-chloropyridin-3-yl)-1-(pyridin-3-ylsulfonyl) -1Hpyrrol-3-yl]-N-methylmethanamine 1.5 fumarate io tert-butyl {[5-(6-chloropyridin-3-yl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methyl}methylcarbamate (100 mg) was dissolved in methanol (8 mL), a 4 mol/L hydrogen chlorideethyl acetate solution (2 mL) was added and the mixture was stirred at 70°C for 30 min. The reaction mixture was is concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=99:1-»19:1) to give a free salt of the title compound. The obtained free salt was dissolved in ethyl acetate (8 mL), a solution of fumaric acid (116 mg) in methanol (2 mL) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 60 mg, 52%).
XH-NMR (DMSO-d6)5: 2.41 (3H, s) , 3.83 (2H, s) , 6.52 (3H, s) ,
6.58 (1H, d, J=1.5 Hz), 7.57-7.63 (2H, m), 7.75-7.78 (2H, m) , 7.85-7.89 (1H, m), 8.20 (1H, d, J=2.3 Hz), 8.61 (1H, d, J=2.6 Hz), 8.88 (1H, dd, J=4.9, 1.5 Hz), 4H not detected.
Example 78
1-[5-(6'-chloro-2,3'-bipyridin-5-yl)-1-(pyridin-3-ylsulfonyl)IH-pyrrol-3-yl]-N-methylmethanamine 0.5 fumarate tert-Butyl {[5-(6'-chloro-2,3'-bipyridin-5-yl)-1(pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]methylJmethylcarbamate (100 mg) was dissolved in ethanol (8 mL), a 4 mol/L hydrogen
210
2015268744 15 Dec 2015 chloride-ethyl acetate solution (2 mL) was added and the mixture was stirred at 70°C for 30 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=99:1—>19:1) to give a free salt of the title compound. The obtained free salt was dissolved in io ethyl acetate (8 mL), a solution of fumaric acid (116 mg) in methanol (2 mL) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 61 mg, 66%).
H-NMR (DM [SO-d6)5: 2.33 (3H, s), 3.69 (2H, s) , 6. ,46 (1H, s) ,
6.58- 6.59 (1H, m), 7.57- -7.62 (1H, m), 7.66-7.70 (2H, m) , 7.83
7.88 (2H, m), 8.15 (1H, d, J=8.3 Hz), 8.52 (1H, d, J=l. 9 Hz) ,
8.57 (1H, d, J=2.3 Hz), 8.60-8.61 (1H, m), 8.86 (1H, d, J=4.9
Hz) , 9.18 (1H, d, J=2.3 Hz), 2H not detected.
Example 79 l-{5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-3yl)sulfonyl]-lH-pyrrol-3-yl]-N-methylmethanamine hydrochloride
By a similar operation as in Example 24 and using tertbutyl ({5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-3yl)sulfonyl]-lH-pyrrol-3-yl]methyl)methylcarbamate (289 mg), the title compound was obtained as colorless crystals (yield 74.2 mg, 29%).
H-NMR (DMSO-ds)6·’ 2.52 (3H, s), 3.94 (3H, s) , 3.99 (2H, s),
6.65 (1H, d, J=1.8 Hz) , 6.99- -7.02 (1H, m), 7.42-7.47 (1H, m),
7.73-7.80 (2H, m), 7.84 (1H, d, 0=1.8 Hz), 8.27-8.28 (1H, m),
30 8.34-8.36 (1H, m) , 9.10 (2H, brs) .
Example 80 (2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)lH-pyrrol-2-ylJphenyl)methanol fumarate
By a similar operation as in Example 70 and using tert35 butyl ({5-[2-fluoro-3-(hydroxymethyl) phenyl]-1-(pyridin-3211
2015268744 15 Dec 2015 ylsulfonyl)-lH-pyrrol-3-yljmethyl)methylcarbamate (238 mg), the title compound, was obtained as colorless crystals (yield 55.3 mg, 22%) .
XH-NMR (DMSO-d6)5: 2.40 (3H, s) , 3.80 (2H, s) , 4.49 (2H, S) ,
6.43 (1H, d, J=1.8 Hz), 6.47 (2H, s) , 6.97-7.02 (1H, m) , 7.177.22 (1H, m), 7.54-7.62 (2H, m) , 7.68 (1H, d, J=1.2 Hz), 7.847.88 (1H, m), 8.56 (1H, d, J=2.1 Hz), 8.86-8.88 (1H, m) , 4H not detected.
Example 81 io 1-(2-fluoro-3-{4-[(methylamino) methyl]-1-(pyridin-3ylsulfonyl)-lH-pyrrol-2-yl}phenyl)ethanol fumarate
By a similar operation as in Example 70 and using tertbutyl ({5-[2-fluoro-3-(1-hydroxyethyl) phenyl]-l-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl}methyljmethylcarbamate (318 mg), the title compound was obtained as colorless crystals (yield • 69.7 mg, 21%).
XH-NMR (DMSO-ds)5: 1.31 (3H, d, J=6.3 Hz), 2.40 (3H, s), 3.81 (2H, s), 4.90 (1H, q, J=6.3 Hz), 6.43 (1H, d, J=1.8 Hz), 6.47 (2H, s), 6.94-7.00 (1H, m) , 7.16-7.22 (1H, m) , 7.58-7.68 (3H,
m), 7.84-7.87 (1H, m) , 8.55 (1H, d, J=2.7 Hz), 8.86-8.88 (1H,
m), 4H not detected.
Example 82
1-[5-(2-fluoro-3-methoxyphenyl)-1-(pyridln-3-ylsulfonyl) -1Hpyrrol-3-yl]-N-methylmethanamine fumarate tert-Butyl {[5-(2-fluoro-3-methoxyphenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methyljmethylcarbamate (475 mg) was dissolved in methanol (20 mL), a 4 mol/L hydrogen chlorideethyl acetate solution (2 mL) was added and the mixture was stirred at 70°C for 20 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (13 mL), fumaric acid (116 mg) was added, and the
212
2015268744 15 Dec 2015 obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 310 mg, 63%). iH-NMR (DMSO-d6)g: 2.41 (3H, s), 3.82 (2H, s) , 3.86 (3H, s) ,
6.45 (1H, d, J=1.7 Hz), 6.48 (2H, s), 6.58-6.63 (1H, m) , 7.105 7.16 (1H, m), 7.24-7.30 (1H, m), 7.59-7.63 (1H, m), 7.70 (1H, d, J=1.5Hz), 7.86-7.90 (1H, m), 8.58 (1H, dd, J=2.3, 0.7 Hz), 8.87-8.89 (1H, m), 3H not detected.
Example 83
1-[5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1Hlo pyrrol-3-yl]-N-methylmethanamine fumarate tert-Butyl {[5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methylJmethylcarbamate (100 mg) was dissolved in methanol (20 mL), a 4 mol/L hydrogen chlorideethyl acetate solution (2 mL) was added and the mixture was stirred at 70°C for 20 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was dissolved in ethanol (6 mL), fumaric acid (49 mg) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 53 mg, 51%).
25 1H-NMR (DMSO-d6)5: 2.45 (3H, s), 3.44 (3H, s), 3.83 (2H, s),
6.36 (1H, d, J=1.5 Hz), 6.48 (2H, s), 6.79-6.86 (2H , m) , 7.44-
7.52 (1H, m), 7.60-7.65 (1H, m), 7.70 (1H, d, J=1.5 Hz) , 7.88-
7.92 (1H, m), 8.56 (1H, d, J=1.9 Hz), 8.88 (1H, dd, J=4. 7 17
Hz), 3H not detected.
Example 84
1-{5-[4-(difluoromethoxy)phenyl]-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl}-N-methylmethanamine fumarate
By a similar operation as in Example 70 and using tertbutyl ({5-[4-(difluoromethoxy)phenyl]-1-(pyridin-335 ylsulfonyl)-lH-pyrrol-3-yl}methyl)methylcarbamate (550 mg), 213
2015268744 15 Dec 2015 the title compound was obtained as colorless crystals (yield 313 mg, 62% for 2 steps).
XH-NMR (DMSO-ds)5: 2.38 (3H, s), 3.78 (2H, s), 6.40 (1H, s) , 6.47 (2H, s), 7.15-7.24 (4H, m), 7.32 (1H, t, J=73.5 Hz),
7.54-7.58 (1H, m), 7.62 (1H, s), 7.77-7.80 (1H, m), 8.50 (1H, d, J=2.4 Hz), 8.84 (1H, d, J=4.5 Hz), 3H not detected.
Example 85
N-methyl-1-[5-(4-methylpyridin-3-yl)-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl]methanamine fumarate io tert-Butyl methyl{[5-(4-methylpyridin-3-yl)-1-(pyridin-3 ylsulfonyl)-lH-pyrrol-3-yl]methyl}carbamate (230 mg) was dissolved in methanol (20 mL), a 4 mol/L hydrogen chlorideethyl acetate solution (2 mL) was added and the mixture was stirred at 70°C for 20 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol (99:1_>95:5) to give a free salt of the title compound. This was dissolved in ethyl acetate (8 mL), a solution of fumaric acid (90 mg) in methanol (2 mL) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 115 mg, 48%).
XH-NMR (DMSO-d6)5: 1·θ9 (3H, s) , 2.43 (3H, s) , 3.84 (2H, s) ,
6.45 (1H, d, J=1.9 Hz), 6.48 (2H, s), 7.29 (1H, d, J=4.9 Hz),
7.60-7.65 (1H, m), 7.73 (1H, d, J=1.9 Hz), 7.81-7.85 (1H, m) ,
7.98 (1H, s), 8.47 (1H, d, J=4.9 Hz), 8.51 (1H, d, J=1.9 Hz),
8.90 (1H, dd, J=4.9, 1.5 Hz), 3H not detected.
Example 86
N-methyl-1- [5-(2-methylpyridin-3-yl)-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl]methanamine fumarate
By a similar operation as in Example 70 and using tert214
2015268744 15 Dec 2015 butyl methyl{[5-(2-methylpyridin-3-yl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methyl}carbamate (278 mg), the title compound was obtained as colorless crystals (yield 93 mg, 32%).
’’H-NMR (DMSO-ds)5: 2.00 (3H, s), 2.43 (3H, s), 3.83 (2H, s) , 6.42 (1H, s), 6.47 (2H, s), 7.20-7.24 (1H, m) , 7.28-7.31 (1H, m), 7.59-7.63 (1H, m) , 7.70 (1H, s), 7.80-7.84 (1H, m), 8.498.51 (2H, m), 8.88-8.90 (1H, m), 3H not detected.
Example 87 io 1-{5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3yl)sulfonyl]-lH-pyrrol-3-yl}-N-methylmethanamine 0.5 fumarate
To a.solution of tert-butyl ({5-(2-fluoropyrldin-3-yl)-1 [(6-methylpyridin-3-yl)sulfonyl]-lH-pyrrol-3yl}methyl)methylcarbamate (86 mg) in ethanol (2 mL) was added a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) at room temperature. The mixture was stirred for 2 hr, and concentrated under reduced pressure. The residue was basified with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a free salt of the title compound as a paleyellow oil. The obtained free salt was dissolved in ethyl acetate (2 mL) and added to a solution (2 mL) of fumaric acid (11.3 mg) in ethanol, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 14 mg, 18%) .
’’H-NMR (DMSO-ds)6: 2.33 (3H, s), 2.56 (3H, s) , 3.68 (2H, s) , 6.44 (1H, s), 6.53 (1H, s), 7.41-7.50 (2H, m), 7.64 (1H, s), 7.74-7.81 (2H, m) , 8.34 (1H, s), 8.48 (1H, s), 2H not detected.
Example 88
1-[4-chloro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl) 215
2015268744 15 Dec 2015 lH-pyrrol-3-yl]-N-methylmethanamine fumarate
4-Chloro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3ylsulfonyl)-lH-pyrrole-3-carbaldehyde (320 mg) was dissolved in a solution of methylamine hydrochloride (591 mg) in methanol (32 mL) and the mixture was stirred for 30 min.
Sodium triacetoxyborohydride (557 mg) was added and the mixture was stirred for 3 hrs. The reaction mixture was concentrated under reduced pressure at 30°C, a saturated aqueous sodium hydrogencarbonate solution was added to the io residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=99:l_>95:5) to give a free salt of the title compound. This was dissolved in ethyl acetate (8 mL), a solution of fumaric acid (102 mg) in methanol (2 mL) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 52 mg, 12%).
XH-NMR (DMSO-d6)5: 2.39 (3H, s) , 3.70 (2H, s) , 6.65 (2H, s) , 7.48-7.53 (1H, m) , 7.63-7.68 (1H, m), 7.81 (1H, s), 7.84-7.96 (2H, m), 8.40-8.42 (1H, m), 8.65 (1H, d, 0=1.9 Hz), 8.93 (1H, dd, 0=4.9, 1.5 Hz), 3H not detected.
Example 89
N-methyl-1-[1-(pyridin-3-ylsulfonyl)-5-(2-thienyl)-lH-pyrrol3-yl]methanamine fumarate
By a similar operation as in Example 70 and using tertbutyl methylf[1-(pyridin-3-ylsulfonyl)-5-(2-thienyl)-1Hpyrrol-3-yl]methyl}carbamate (315 mg), the title compound was obtained as colorless crystals (yield 165 mg, 51%) .
XH-NMR (EMSO-d6)5: 2.43 (3H, s) , 3.83 (2H, s), 6.47 (2H, s) , 6.52 (1H, d, 0=1.8 Hz), 7.07-7.12 (2H, m) , 7.55-7.62 (2H, m), 7.70 (1H, d, 0=1.8 Hz), 7.84-7.88 (1H, m), 8.53-8.54 (1H, m), 8.83-8.85 (1H, m), 3H not detected.
Example 90
216
2015268744 15 Dec 2015
N-methyl-1-[5-(3-methylpyridin-2-yl)-1-(pyridin-3-ylsulfonyl) lH-pyrrol-3-yl]methanamine fumarate
By a similar operation as in Example 70 and using tertbutyl methyl{[5-(3-methylpyridin-2-yl)-1-(pyridin-35 ylsulfonyl)-lH-pyrrol-3-yl]methyl}carbamate (229 mg), the title compound was obtained as colorless crystals (yield 124 mg, 53%) .
^-NMR (DMSO-d5)6: 2.18 (3H, s) , 2.44 (3H, s) , 3.86 (2H, s) ,
6.46 (2H, s), 6.52 (1H, d, J=1.8 Hz), 7.32-7.36 (1H, m) , 7.66 ίο Ί.Ί4 (3H, m), 8.17-8.21 (1H, m) , 8.28-8.30 (1H, m) , 8.87-8.90 (2H, m), 3H not detected.
Example 91
2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)lH-pyrrol-2-yl}benzonitrile fumarate is By a similar operation as in Example 70 and using tertbutyl {[5-(3-cyano-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)lH-pyrrol-3-yl]methyl}methylcarbamate (170 mg), the title compound was obtained as colorless crystals (yield 96 mg,
74%) .
1H-NMR (DMSO-d6)5: 2.39 (3H, s), 3.80 (2H, s) , 6.47 (2H, s) , 6.59 (1H, d, J=1.5Hz), 7.43-7.48 (1H, m), 7.52-7.57 (1H, m) , 7.60-7.65 (1H, m), 7.76 (1H, d, J=1.8 Hz), 7.89-7.93 (1H, m) , 8.02-8.07 (1H, m), 8.59-8.60 (1H, m), 8.89-8.91 (1H, m), 3H not detected.
Example 92
4—{4—[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-IH-pyrrol 2-yl}thiophene-3-carbonitrile fumarate
By a similar operation as in Example 70 and using tertbutyl {[5-(4-cyano-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H30 pyrrol-3-yl]methyl}methylcarbamate (297 mg), the title compound was obtained as colorless crystals (yield 155 mg,
50%) .
XH-NMR (DMSO-de)§: 2.41 (3H, s), 3.84 (2H, s), 6.47 (2H, s), 6.56 (1H, d, J=2.1 Hz), 7.59-7.74 (1H, m), 7.67 (1H, d, J=3.0
Hz), 7.73-7.74 (1H, m) , 7.86-7.90 (1H, m), 8.57-8.59 (2H, m) , 217
2015268744 15 Dec 2015 io
8.87-8.89 (1H, m), 3H not detected.
The structures of the compounds described in Reference
Examples are shown in Tables 1-14.
218
Table 1
2015268744 15 Dec 2015
Figure AU2015268744B2_D0025
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Figure AU2015268744B2_D0026
VZ d2
Figure AU2015268744B2_D0027
'F
Figure AU2015268744B2_D0028
X / /CF3
W” vz
A
Figure AU2015268744B2_D0029
H
H
H
Br
H CO2Et
H CO2Et
Me CO2Me
H CO2Et
H CO2Et
Me CO2Me
H CO2Et
H CH2OH
Me CH2OH
H CHO
Me CHO
H CHO
H CHO
H CO2Me
Me CO2Me
H CO2Et
H CO2Me
C!
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
219
Table 2
2015268744 15 Dec 2015
Figure AU2015268744B2_D0030
Ref. Ex. No. R1a R2a R3a R4a R5a
23 H Br Me CO2Me H
24 H Br H CO2Et Me
36 Ol—s'Oa N—J H CO2Et H
37 N=\ / Me—$—SO2 ........... O- H CO2Et H
38 h2n-^^—so2 o- H CO2Et H
39 ζΡ^ζ°! O- H COaEt H
40 O~s°2 o- H CO2Et H
41 Br H CO2Me H
42 CM Br Me CO2Me H
43 O~si°2 H H CO2Et . Me
44 Q-A Br H CO2Et Me
45 O~^2 O“ H CO2Et Me
46 CM Br H CH2OH H
47 CM H H ch2oh Me
48 Br H CHO H
49 CH2 Br Me CHO H
50 H o~ Me CHO H
220
Table 3
2015268744 15 Dec 2015
Figure AU2015268744B2_D0031
221
Table 4
Ref. Ex. No.
R1a
R2a a 3a R4a R5a
2015268744 15 Dec 2015 R3a R4a
R2a R1a RSa
Figure AU2015268744B2_D0032
W dso,
Figure AU2015268744B2_D0033
/
Figure AU2015268744B2_D0034
Me y—SO2
O-A
Br
Br
Br
Br
Me
Me
Me
Me
H
H
H
H
CHO
CHO
CHO
CHO
CH2NHMe
CH2N^e z Boc CH2N'Boc CH2N'Boc
H
H
H
H
V/ oO-
CP d
FX~y~ CH=N:b’o °H=N'Boc H H “Co H CH2<^c
H CHX^
222
R3ax
14a
R23' .RSa
R3a R4a R5a
2015268744 15 Dec 2015
Table 5
R1a
Figure AU2015268744B2_D0035
H
H
H
H
H
H
H
H
H
H
CH2N:
•Me 'Boc ch2nC
Me
Boc ch2nC ch2n:
CH2N
Me
Boc .Me ’Boc xMe
Boc
CH2N ch2n:
Me 'Boc
Me ’Boc ch2nC,
CH2N:
Me
Boc .Me ’Boc ch2nC
Me
Boc ch2nC
CH2N:
Me
Boc
Me
Boc ch2nC
Me
Boc
H
H
H
H
H
H
H
H
H
Me
223
Table 6
2015268744 15 Dec 2015
R3i >4a
Rla
Figure AU2015268744B2_D0036
F CO2Me ci
100
101
102
Figure AU2015268744B2_D0037
h ry~
H CO2Et
H CO2Me
F CO2Me
103
104
105
106
107
111
112 iV
Figure AU2015268744B2_D0038
ch2oh ch2oh
CHO
CHO
CHO
H
CHO
H
H
H
H
H
H
H
224
Table 7
R23' RSa
2015268744 15 Dec 2015 R3a R4a R1a
Figure AU2015268744B2_D0039
. 114
115
116
122
123
124
125
126
127
128
Figure AU2015268744B2_D0040
F3C
Me
Figure AU2015268744B2_D0041
F3C
Me
Figure AU2015268744B2_D0042
Cl CHO H
F CHO H
F CHO H
H CO2Et H
H CO2Et H
H COzEt H
F CO2Me H
H CHO H
H CHO H
H CHO H
225
Table 8
Ref. Ex. No. R1a R2a R3a R43 RSa
2015268744 15 Dec 2015
Figure AU2015268744B2_D0043
Figure AU2015268744B2_D0044
226
Table 9
R2i
RSa
R1a
Ref. Ex. No. R1a
R2a R3a R4a R5a
2015268744 15 Dec 2015
R®\
139
140
141
142
143
144
145
146
Figure AU2015268744B2_D0045
CHO
CHO
CHO Cl
CH2N z-Me
Boc ch2nC
CH2N:
CH2N
Me 'Boc
Me 'Boc xMe
Boo
CH2N:
Me ‘Boc
227
Table 10
2015268744 15 Dec 2015
Figure AU2015268744B2_D0046
228
Table 11
R2a .R5a
R1a
2015268744 15 Dec 2015
R3a
Figure AU2015268744B2_D0047
229
Table 12
R1a
Ref. Ex. No. R1a R2a R3a R4a RSa
2015268744 15 Dec 2015 R2a·
R4a
R5a
Figure AU2015268744B2_D0048
OMe
CHsN:
Me ’Boc ch2nC
Me
Boc ch2nC
Me
Boc ch2nC
Me ’Boc ch2nC
Me
Boc
CH2N^
Me
Boc ch2nC
Me ’Boc ch2nC
Me
Boc ch2nC
CH2N:
CH2N:
Me
Boc
Me ‘Boc .Me ’Boc
230
Table 13
R2i •RSa
R1a
Ref. Ex. No. R1a
R2a r33 r43 R5a
2015268744 15 Dec 2015 R3a R4a
180
181
183
187
188
189
190
191
192
194
196
Figure AU2015268744B2_D0049
CH2ri
Me 'Boc ch2nC
Me
Boc ch2nC
CH2N
Me
Boo xMe ''Boc
CH2N' •Me ‘Boo
CHO
CHO
CHO
CHO
CH2N zMe ''Boc
CH2N •Me 'Boc
H
H
H
H
H
H
H
H
H
H
H
231 R2a·
RSa
R1a
Ref. Ex. No. R1a
R2a RSa R4a
2015268744 15 Dec 2015
Table 14
197
198
199
200 R3a R4a
Figure AU2015268744B2_D0050
CH2N'
CH2N
CH2N'
CH2N •Me
Boc •Me ’Boc .Me 'Boc xMe
Boo RSa
H
H
H
H
The structures of the compounds described in Examples are 5 shown in Tables 15-23.
232
Table 15
2015268744 15 Dec 2015
Figure AU2015268744B2_D0051
233
Table 16
2015268744 15 Dec 2015
Figure AU2015268744B2_D0052
234
Table 17
2015268744 15 Dec 2015
Figure AU2015268744B2_D0053
Ex. No. R1b ' R2b R3b R4b addition salt
Figure AU2015268744B2_D0054
235
Table 18
2015268744 15 Dec 2015
Figure AU2015268744B2_D0055
236
Table 19
2015268744 15 Dec 2015
Figure AU2015268744B2_D0056
237
Table 20
Ex. No. R1b R2b R3b R4b addition salt
5268744 15 Dec 2015
Figure AU2015268744B2_D0057
Figure AU2015268744B2_D0058
238
Table 21
2015268744 15 Dec 2015
Rk R*
Λ 5
R2C R R1c
Figure AU2015268744B2_D0059
SMe
Figure AU2015268744B2_D0060
Figure AU2015268744B2_D0061
O2 \J~
SO2IV &
CN
O
H CH2NHMe
H CH2NHMe
Figure AU2015268744B2_D0062
HO2C
O^s>°2
Figure AU2015268744B2_D0063
Me
H CH2NHMe h
C02H
Figure AU2015268744B2_D0064
H CH2NHMe H
CN CH2NHMe H
H CH2NHMe CN
H CH2NHMe H
H02'
H02i
HO;
HO2'
H02'
H CH2NHMe H 0.5
CO,H
C02H co2h
C02H co2h
239
Table 22
Ex. No. R1°
R20 R30 R4c R5g addition salt
2015268744 15 Dec 2015 R3c r4o r2o^i< rS
Ri°
Figure AU2015268744B2_D0065
H CH2NHMe h
H CH2NHMe H
H CH2NHMe
HOHO;
H CH2NHMe
HO2'
CH2NHMe H 1.5
Figure AU2015268744B2_D0066
H CH2NHMe H HCI co2h
COjH
H CH2NHMe
Figure AU2015268744B2_D0067
HO2i
CH2NHMe H 0.5
CO2H
C02H
H CH2NHMe
H CH2NHMe
Figure AU2015268744B2_D0068
H CH2NHMe H
HO;
CO2H
240
Table 23
2015268744 15 Dec 2015 R3o r4o
R2c'^'f<'R5
R1c
Figure AU2015268744B2_D0069
e^O~s/
Figure AU2015268744B2_D0070
W~s°2
Figure AU2015268744B2_D0071
ddA
N u
HO2'
H CH2NHMe H 0.5
Cl CH2NHMe H
H CH2NHMe H
CO2H
HO2i
HOco2h co2h
H CH2NHMe
H CH2NHMe
Figure AU2015268744B2_D0072
Figure AU2015268744B2_D0073
HOH CH2NHMe H
CO2H
241
2015268744 15 Dec 2015
Experimental Example 1
Proton potassium - adenosine triphosphatase (H+, K+-ATPase) inhibitory activity test
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, immersed in 3 mol/L brine, and the surface of the mucous membrane was wiped with a paper towel. The gastric mucous io membrane was detached, chopped, and homogenized in a 0.25 mol/L saccharose solution (pH 6.8) containing 1 mmol/L EDTA and 10 mmol/L tris-hydrochloric acid using polytron (Kinematica). The obtained homogenate was centrifuged at 20,000xg for 30 min and the supernatant was centrifuged at
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 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.
To 40 μΕ of a 50 mmol/L HEPES-tris buffer (5 mmol/L magnesium chloride, 10 mmol/L potassium chloride, 10 μριοΙ/L valinomycin, pH=6.5) containing 2.5 μg/mL (based on the protein concentration) of the enzyme standard product was added a test compound (5 μΕ) 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 μΕ of a 2 mmol/L adenosine triphosphate tris salt solution (50 mmol/L HEPEStris buffer (5 mmol/L magnesium chloride, pH 6.5)). The enzyme reaction was carried out at 37°C for 20 min, and 15 μΕ 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 242
2015268744 15 Dec 2015 quench the reaction. After allowing to stand at room temperature for 15 min, the resulting reaction product of inorganic phosphorus with malachite green was colorimetrically determined at a wavelength of 610 nm. In addition, the amount of the inorganic phosphoric acid in the reaction solution free of potassium chloride was measured in the same manner, which was subtracted from the inorganic phosphoric acid amount in the presence of potassium chloride to determine the proton, potassium - adenosine triphosphatase activity. The inhibitory io rate (%) was determined from the activity value of the control and the activity values of various concentrations of the test compound, and the 50% inhibitory concentration (IC5o) of the proton, potassium - adenosine triphosphatase was determined.
The results are shown in Table 24.
Experimental Example 2
Human liver cancer-derived cell line HepG2 (ATCC No. HB8065) 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),
2 mmol/L L-glutamine (Invitrogen), 50 IU/mL penicillin (Invitrogen) and 50 qg/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
50 qg/mL streptomycin to a final concentration of DMSO of 0.1%. HepG2 (2χ104 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 in
Table 24 (n>3, average value + SD) as a relative value (%) to control (without addition of drug) at 30 μΜ·
243
2015268744 19 Feb 2016
Table 24
Example No. H+/K+-ATPase inhibitory activity (IC50, nM) ATP content (%, 30 μΜ)
2 13 45.2
5 65 73.9
8 22 87.9
29 41 71.5
41 43 86.7
44 48 78.5
47 58 81.8
74 210 95.2
From the results of Table 24, it is clear that compound (I) of the present invention has a superior H+/K+-ATPase inhibitory activity, and further shows low cytotoxicity.
Industrial Applicability
Since compound (I) of the present invention shows a superior proton pump inhibitory effect (while conventional proton pump inhibitors such as omeprazole, lansoprazole etc.
form a covalent bond with a cysteine residue of H+/K+-ATPase and irreversibly inhibit the enzyme activity, since compound (I) inhibits the proton pump (H+/K+-ATPase) activity reversibly and in a K+ antagonist inhibitory manner to consequently suppress acid secretion, it is sometimes referred is to as a potassium-competitive acid blocker: P-CAB or an acid pump antagonist (ACPA or APA)), it can provide a clinically useful pharmaceutical composition for the prophylaxis and/or treatment of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper
7436033_1 (GHMatters) P76750.AU.2 JENNYP
244
2015268744 15 Jan 2018 gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress. Since compound (I) shows low toxicity and is superior in watersolubility, in vivo kinetics and efficacy expression, it is useful as a pharmaceutical composition. Moreover, since compound (I) is stable even under acidic conditions, which enables oral administration of the compound as a conventional tablet and the like without formulating an enteric-coated preparation. This has a consequence that the preparation of io tablet and the like can be made smaller, which is advantageous in that it is easily swallowed by patients having difficulty in swallowing, particularly the elderly and children. In addition, since a sustained release effect afforded by enteric-coated preparations is absent, expression of a gastric acid secretion-suppressive action is rapid, and alleviation of symptoms such as pain and the like is rapid.
This application is based on patent application Nos. 2005-250356 and 2006-100626 filed in Japan, the contents of which are incorporated in full herein by this reference.
It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.
In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word comprise or variations such as comprises or comprising is used in an inclusive sense,
i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.
9793697_1 (GHMatters) P76750.AU.2
245

Claims (24)

  1. 2015268744 25 Jan 2018
    1. A compound represented by the formula (I):
    R' ,5 ,3
    Λ wherein R1 is an aromatic or saturated or unsaturated nonaromatic monocyclic nitrogen-containing heterocyclic group containing, as a ring-constituting atom, at least one nitrogen atom and being optionally condensed with a benzene ring or an aromatic or non-aromatic heterocycle, the monocyclic nitrogencontaining heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has 1 to 5 substituent(s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) Ci-6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) monoCg-i4 arylamino, (15) mono-C7_i6 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) C1-6 alkoxy-carbonyl, (24) C6-14 aryloxycarbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 arylcarbamoyl, (30) C1-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32) C1-6 alkylsulf inyl, (33) C6-14 arylsulf inyl, (34) formylamino, (35) C1-6 alkyl-carbonylamino, (36) C6-14 aryl-carbonylamino, (37) C1-6 alkoxy-carbonylamino, (38) C1-6 alkylsulf onylamino, (39) Cg-i4 arylsulf onylamino, (40) C1-6 alkyl-carbonyloxy, (41) C6-14 aryl-carbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) monoC1-6 alkyl-carbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) C6-14 aryl-carbamoyloxy, (46) a 5- to 7-membered saturated
    9915521_1 (GHMatters) P76750.AU.2
    246
    2015268744 25 Jan 2018 cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, 5 besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 alkylenedioxy, (49) C3-7 cycloalkyl, (50) Ci-6 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6 alkenyl group optionally having 1 to 3 halogen atoms, (52) a 10 C2-6 alkynyl group, and (53) a Ci-6 alkyl group substituted by 1 to 3 hydroxy, R2 is (i) a C6-14 aryl group optionally having 1 to 5 substituent(s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) Ci-6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, 15 (7) C7-16 aralkyloxy, (8) mercapto, (9) Ci-6 alkylthio optionally having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) monoCg-i4 arylamino, (15) mono-C7_i6 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino,
    20 (19) formyl, (20) Ci-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) Ci-6 alkoxy-carbonyl, (24) C6-14 aryloxycarbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 arylcarbamoyl, (30) Ci-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32)
    25 Ci-6 alkylsulfinyl, (33) C6-14 arylsulfinyl, (34) formylamino, (35) Ci-6 alkyl-carbonylamino, (36) C6-14 aryl-carbonylamino, (37) Ci-6 alkoxy-carbonylamino, (38) Ci-6 alkylsulfonylamino, (39) C6-14 arylsulf onylamino, (40) Ci-6 alkyl-carbonyloxy, (41) C6-14 aryl-carbonyloxy, (42) Ci-6 alkoxy-carbonyloxy, (43) mono25 Ci-6 alkyl-carbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45)
    C6-14 aryl-carbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a
    25 5- to 10-membered aromatic heterocyclic group containing,
    9915521_1 (GHMatters) P76750.AU.2
    247
    2015268744 25 Jan 2018 besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 alkylenedioxy, (49) C3-7 cycloalkyl, (50) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6 5 alkenyl group optionally having 1 to 3 halogen atoms, (52) a C2-6 alkynyl group, and (53) a C1-6 alkyl group substituted by 1 to 3 hydroxy, (ii) a thienyl group optionally having 1 to 4 substituent(s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) C1-6 alkoxy 10 optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) monoCg-i4 arylamino, (15) mono-C7_i6 aralkylamino, (16) di-Ci-6 15 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) C1-6 alkoxy-carbonyl, (24) C6-14 aryloxycarbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 aryl20 carbamoyl, (30) C1-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32)
    C1-6 alkylsulfinyl, (33) C6-14 arylsulfinyl, (34) formylamino, (35) C1-6 alkyl-carbonylamino, (36) C6-14 aryl-carbonylamino, (37) C1-6 alkoxy-carbonylamino, (38) C1-6 alkylsulfonylamino, (39) C6-14 arylsulf onylamino, (40) C1-6 alkyl-carbonyloxy, (41)
  2. 25 C6-14 aryl-carbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) monoC1-6 alkyl-carbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) C6-14 aryl-carbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected
    20 from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 alkylenedioxy, (49) C3-7 cycloalkyl, (50) C1-6
    25 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6
    9915521_1 (GHMatters) P76750.AU.2
    248
    2015268744 25 Jan 2018 alkenyl group optionally having 1 to 3 halogen atoms, (52) a C2-6 alkynyl group, and (53) a C1-6 alkyl group substituted by 1 to 3 hydroxy, or (iii) a pyridyl group optionally having 1 to 4 substituent (s) selected from the group consisting of (1) a 5 halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) mono10 C6-14 arylamino, (15) mono-C7_i6 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) C1-6 alkoxy-carbonyl, (24) C6-14 aryloxycarbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 15 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 arylcarbamoyl, (30) C1-6 alkylsulf onyl, (31) C6-14 arylsulfonyl, (32)
    C1-6 alkylsulf inyl, (33) C6-14 arylsulf inyl, (34) formylamino, (35) C1-6 alkyl-carbonylamino, (36) C6-14 aryl-carbonylamino, (37) C1-6 alkoxy-carbonylamino, (38) C1-6 alkylsulf onylamino,
    20 (39) Cg-i4 arylsulf onylamino, (40) C1-6 alkyl-carbonyloxy, (41)
    C6-14 aryl-carbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) monoC1-6 alkyl-carbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) C6-14 aryl-carbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom
    25 and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen 30 atom, (48) C1-3 alkylenedioxy, (49) C3-7 cycloalkyl, (50) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6 alkenyl group optionally having 1 to 3 halogen atoms, (52) a C2-6 alkynyl group, and (53) a C1-6 alkyl group substituted by 1 to 3 hydroxy, R3 and R4 are each a hydrogen atom, or one of R3
    25 and R4 is a hydrogen atom and the other is (i) a C1-4 alkyl
    9915521_1 (GHMatters) P76750.AU.2
    249
    2015268744 25 Jan 2018 group optionally having 1 to 3 substituent(s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) Ci_6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) 5 mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) mono-C6-i4 arylamino, (15) monoC7-16 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 10 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) Ci6 alkoxy-carbonyl, (24) C6-14 aryloxy-carbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 aryl-carbamoyl, (30) C1-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32) C1-6 alkylsulf inyl, 15 (33) Cg-i4 arylsulf inyl, (34) formylamino, (35) C1-6 alkylcarbonylamino, (36) Cg-i4 aryl-carbonylamino, (37) C1-6 alkoxycarbonylamino, (38) C1-6 alkylsulf onylamino, (39) C6-14 arylsulf onylamino, (40) C1-6 alkyl-carbonyloxy, (41) C6-14 arylcarbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) mono-Ci-6 alkyl25 carbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) C6-14 arylcarbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to
    25 10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 alkylenedioxy, and (49) C3-7 cycloalkyl, (ii) an acyl group selected from the group consisting of a C1-7 alkanoyl group, a
    25 Cg-i4 aryl-carbonyl group, a C1-6 alkoxy-carbonyl group, a C6-14 aryloxy-carbonyl group, a C7-19 aralkyl-carbonyl group, a C7-19 aralkyloxy-carbonyl group, a 5- or 6-membered heterocyclecarbonyl group or condensed heterocycle-carbonyl group thereof, and a 5- or 6-membered heterocycle-acetyl group, wherein when
    25 the acyl group is a C1-7 alkanoyl group or a C1-6 alkoxy-carbonyl
    9915521_1 (GHMatters) P76750.AU.2
    250
    2015268744 25 Jan 2018 group, the acyl group is optionally substituted by 1 to 3 C1-4 alkylthio groups, halogen, C1-6 alkoxy groups, a nitro group,
    C1-6 alkoxy-carbonyl groups, mono- or di-Ci-6 alkylamino groups, C1-6 alkoxyimino groups or hydroxyimino, wherein when the acyl 5 group is a C6-14 aryl-carbonyl group, a C6-14 aryloxy-carbonyl group, a C7-19 aralkyl-carbonyl group, a C7-19 aralkyloxycarbonyl group, a 5- or 6-membered heterocycle-carbonyl group or a 5or 6-membered heterocycle-acetyl group, the acyl group is optionally substituted by 1 to 5 C1-6 alkyl groups, C3-6 10 cycloalkyl groups, C2-6 alkenyl groups, C2-6 alkynyl groups, C1-6 alkoxy groups, C1-7 alkanoyl groups, C6-14 aryl-carbonyl groups, C1-6 alkoxy-carbonyl groups, C6-14 aryloxy-carbonyl groups, C7-19 aralkyl-carbonyl groups, C7-19 aralkyloxy-carbonyl groups, nitro, amino, hydroxy, cyano, sulfamoyl, mercapto, halogen, or C1-4 15 alkylthio groups, (iii) a halogen atom, (iv) a cyano group or (v) a nitro group, and R5 is a C1-6 alkyl group, or a salt thereof;
    excluding 1- [5- (2-fluorophenyl)-1-(pyridin-3-ylsulfonyl) -1Hpyrrol-3-yl]-N-methylmethanamine or a salt thereof.
    2. The compound according to claim 1 and represented by the wherein R1 is a monocyclic nitrogen-containing heterocyclic 25 group optionally condensed with a benzene ring or a heterocycle, the monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has 1 to 5 substituent(s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) 30 cyano, (4) hydroxy, (5) C1-6 alkoxy optionally having 1 to 3
    9915521_1 (GHMatters) P76750.AU.2
    251
    2015268744 25 Jan 2018 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) mono-C6-i4 arylamino, (15) mono5 C7-16 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) Ci6 alkoxy-carbonyl, (24) C6-14 aryloxy-carbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 10 alkyl-carbamoyl, (29) C6-14 aryl-carbamoyl, (30) C1-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32) C1-6 alkylsulfinyl, (33) Cg-i4 arylsulfinyl, (34) formylamino, (35) C1-6 alkylcarbonylamino, (36) Cg-i4 aryl-carbonylamino, (37) C1-6 alkoxycarbonylamino, (38) C1-6 alkylsulfonylamino, (39) C6-14 15 arylsulfonylamino, (40) C1-6 alkyl-carbonyloxy, (41) C6-14 arylcarbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) mono-Ci-6 alkylcarbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) C6-14 arylcarbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon
    20 atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3
    25 alkylenedioxy, (49) C3-7 cycloalkyl, (50) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6 alkenyl group optionally having 1 to 3 halogen atoms, (52) a C2-6 alkynyl group, and (53) a C1-6 alkyl group substituted by 1 to 3 hydroxy, R2 is (i) a C6-14 aryl group optionally having 1 to 5 30 substituent (s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16
    55 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) mono9915521_1 (GHMatters) P76750.AU.2
    252
    2015268744 25 Jan 2018
    Cg-i4 arylamino, (15) mono-C7_i6 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-Cg-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) Ci_6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) Ci-6 alkoxy-carbonyl, (24) C6-14 aryloxy5 carbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 arylcarbamoyl, (30) Ci-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32) Ci-6 alkylsulf inyl, (33) C6-14 arylsulf inyl, (34) formylamino, (35) Ci-6 alkyl-carbonylamino, (36) C6-14 aryl-carbonylamino, 10 (37) Ci-6 alkoxy-carbonylamino, (38) Ci_6 alkylsulf onylamino, (39) Cg-i4 arylsulf onylamino, (40) Ci_6 alkyl-carbonyloxy, (41) C6-14 aryl-carbonyloxy, (42) Ci-6 alkoxy-carbonyloxy, (43) monoCi_6 alkyl-carbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) C6-14 aryl-carbamoyloxy, (46) a 5- to 7-membered saturated 15 cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms
    2o selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 alkylenedioxy, (49) C3-7 cycloalkyl, (50) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6 alkenyl group optionally having 1 to 3 halogen atoms, (52) a C2-6 alkynyl group, and (53) a C1-6 alkyl group substituted by 1
    25 to 3 hydroxy, or (ii) a thienyl group optionally having 1 to 4 substituent (s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3) cyano, (4) hydroxy, (5) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally 30 having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) monoCg-i4 arylamino, (15) mono-C7_i6 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl,
    55 (22) carboxyl, (23) C1-6 alkoxy-carbonyl, (24) C6-14 aryloxy9915521_1 (GHMatters) P76750.AU.2
    253
    2015268744 25 Jan 2018 carbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6 alkyl-carbamoyl, (29) C6-14 arylcarbamoyl, (30) Ci-6 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32)
    Ci-6 alkylsulfinyl, (33) C6-14 arylsulfinyl, (34) formylamino, 5 (35) Ci-6 alkyl-carbonylamino, (36) C6-14 aryl-carbonylamino, (37) Ci-6 alkoxy-carbonylamino, (38) Ci_6 alkylsulfonylamino, (39) Cg-i4 arylsulf onylamino, (40) Ci_6 alkyl-carbonyloxy, (41) C6-14 aryl-carbonyloxy, (42) Ci-6 alkoxy-carbonyloxy, (43) monoCi_6 alkyl-carbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) 10 C6-14 aryl-carbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, 15 besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 alkylenedioxy, (49) C3-7 cycloalkyl, (50) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (51) a C2-6 alkenyl group optionally having 1 to 3 halogen atoms, (52) a
    20 C2-6 alkynyl group, and (53) a C1-6 alkyl group substituted by 1 to 3 hydroxy, R3 and R4 are each a hydrogen atom, or one of R3 and R4 is a hydrogen atom and the other is (i) a C1-4 alkyl group optionally having 1 to 3 substituent(s) selected from the group consisting of (1) a halogen atom, (2) nitro, (3)
    25 cyano, (4) hydroxy, (5) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (6) C6-14 aryloxy, (7) C7-16 aralkyloxy, (8) mercapto, (9) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (10) C6-14 arylthio, (11) C7-16 aralkylthio, (12) amino, (13) mono-Ci-6 alkylamino, (14) mono-C6-i4 arylamino, (15) mono25 C7-16 aralkylamino, (16) di-Ci-6 alkylamino, (17) di-C6-i4 arylamino, (18) di-C7_i6 aralkylamino, (19) formyl, (20) C1-6 alkyl-carbonyl, (21) C6-14 aryl-carbonyl, (22) carboxyl, (23) Ci6 alkoxy-carbonyl, (24) C6-14 aryloxy-carbonyl, (25) carbamoyl, (26) thiocarbamoyl, (27) mono-Ci-6 alkyl-carbamoyl, (28) di-Ci-6
    25 alkyl-carbamoyl, (29) C6-14 aryl-carbamoyl, (30) C1-6
    9915521_1 (GHMatters) P76750.AU.2
    254
    2015268744 25 Jan 2018 alkylsulfonyl, (31) C6-14 arylsulfonyl, (32) C1-6 alkylsulfinyl, (33) Cg-i4 arylsulf inyl, (34) formylamino, (35) C1-6 alkylcarbonylamino, (36) C6-14 aryl-carbonylamino, (37) C1-6 alkoxycarbonylamino, (38) C1-6 alkylsulfonylamino, (39) C6-14 5 arylsulf onylamino, (40) C1-6 alkyl-carbonyloxy, (41) C6-14 arylcarbonyloxy, (42) C1-6 alkoxy-carbonyloxy, (43) mono-Ci-6 alkylcarbamoyloxy, (44) di-Ci-6 alkyl-carbamoyloxy, (45) C6-14 arylcarbamoyloxy, (46) a 5- to 7-membered saturated cyclic amino optionally containing, besides one nitrogen atom and carbon 10 atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, (48) C1-3 15 alkylenedioxy, and (49) C3-7 cycloalkyl, (ii) an acyl group selected from the group consisting of a C1-7 alkanoyl group, a C6-14 aryl-carbonyl group, a C1-6 alkoxy-carbonyl group, a C6-14 aryloxy-carbonyl group, a C7-19 aralkyl-carbonyl group, a C7-19 aralkyloxy-carbonyl group, a 5- or 6-membered heterocycle22 carbonyl group or condensed heterocycle-carbonyl group thereof, and a 5- or 6-membered heterocycle-acetyl group, wherein when the acyl group is a C1-7 alkanoyl group or a C1-6 alkoxy-carbonyl group, the acyl group is optionally substituted by 1 to 3 C1-4 alkylthio groups, halogen, C1-6 alkoxy groups, a nitro group,
    25 C1-6 alkoxy-carbonyl groups, mono- or di-Ci-6 alkylamino groups,
    C1-6 alkoxyimino groups or hydroxyimino, wherein when the acyl group is a C6-14 aryl-carbonyl group, a C6-14 aryloxy-carbonyl group, a C7-19 aralkyl-carbonyl group, a C7-19 aralkyloxycarbonyl group, a 5- or 6-membered heterocycle-carbonyl group or a 530 or 6-membered heterocycle-acetyl group, the acyl group is optionally substituted by 1 to 5 C1-6 alkyl groups, C3-6 cycloalkyl groups, C2-6 alkenyl groups, C2-6 alkynyl groups, C1-6 alkoxy groups, C1-7 alkanoyl groups, C6-14 aryl-carbonyl groups, C1-6 alkoxy-carbonyl groups, C6-14 aryloxy-carbonyl groups, C7-19
    25 aralkyl-carbonyl groups, C7-19 aralkyloxy-carbonyl groups, nitro,
    9915521_1 (GHMatters) P76750.AU.2
    255
    2015268744 25 Jan 2018 amino, hydroxy, cyano, sulfamoyl, mercapto, halogen, or C1-4 alkylthio groups, (iii) a halogen atom, (iv) a cyano group or (v) a nitro group, and R5 is a C1-6 alkyl group, or a salt thereof.
  3. 3. The compound of claim 1 or 2, wherein R1 is a monocyclic nitrogen-containing heterocyclic group.
  4. 4. The compound of claim 1 or 2, wherein the monocyclic
    10 nitrogen-containing heterocyclic group is a pyridyl group.
  5. 5. The compound of claim 1 or 2, wherein R2 is a phenyl group optionally substituted by 1 to 5 substituents selected from (i) a halogen atom and (ii) a C1-6 alkyl optionally substituted
    15 by 1 to 5 halogen atoms.
  6. 6. The compound of claim 1, wherein R2 is a pyridyl group optionally substituted by 1 to 4 substituent(s) selected from C1-6 alkyl, a halogen atom, C1-6 alkoxy, cyano, acyl, nitro and
    20 amino.
  7. 7. The compound of claim 1 or 2, wherein R3 and R4 are each a hydrogen atom.
    25
  8. 8. The compound of claim 1 or 2, wherein R5 is a methyl group.
  9. 9. 1-{5-(2-Fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]lH-pyrrol-3-yl}-N-methylmethanamine or a salt thereof.
    30
  10. 10. 1-[4-Fluoro-5-phenyl-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-3yl]-N-methylmethanamine or a salt thereof.
  11. 11. N-Methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3ylsulfonyl)-lH-pyrrol-3-yl]methanamine or a salt thereof.
    9915521_1 (GHMatters) P76750.AU.2
    256
    2015268744 25 Jan 2018
  12. 12. 1- [5- (2-Fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine or a salt thereof.
  13. 13. N-Methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)5 lH-pyrrol-3-yl]methanamine or a salt thereof.
  14. 14. A prodrug of the compound of claim 1 or 2.
  15. 15. A pharmaceutical composition comprising the compound of io claim 1 or 2 or a prodrug thereof.
  16. 16. A pharmaceutical composition comprising 1-[5-(2fluorophenyl)-1-(pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]-Nmethylmethanamine or a salt thereof or a prodrug thereof.
  17. 17. The pharmaceutical composition of claim 15 or 16, which is an acid secretion inhibitor.
  18. 18. The pharmaceutical composition of claim 15 or 16, which is
    20 a potassium-competitive acid blocker.
  19. 19. The pharmaceutical composition of claim 15 or 16, which is an agent for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis,
    25 reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive
    30 stress.
  20. 20. A method of treating or preventing peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux
    35 disease (Symptomatic GERD), functional dyspepsia, gastric
    9915521_1 (GHMatters) P76750.AU.2
    257
    2015268744 25 Jan 2018 cancer, stomach MALT lymphoma, or gastric hyperacidity; or a method of inhibiting upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress, which comprises administering an effective
    5 amount of the compound of claim 1 or 2 or a prodrug thereof to a mammal.
  21. 21. Use of the compound of claim 1 or 2 or a prodrug thereof for the production of a pharmaceutical composition for the io treatment or prophylaxis of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (Symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper
    15 gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress.
  22. 22. A method of treating or preventing peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis,
    20 reflux esophagitis, symptomatic gastroesophageal reflux disease (Symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or a method of inhibiting upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or
    25 invasive stress, which comprises administering an effective amount of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine or a salt thereof or a prodrug thereof to a mammal.
    30
  23. 23. Use of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1Hpyrrol-3-yl]-N-methylmethanamine or a salt thereof or a prodrug thereof for the production of a pharmaceutical composition for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis,
    35 reflux esophagitis, symptomatic gastroesophageal reflux
    9915521_1 (GHMatters) P76750AU.2
    258
    2015268744 25 Jan 2018 disease (Symptomatic GERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive
    5 stress.
  24. 24. A compound according to claim 1 and represented by the 10 wherein R1 is a pyridyl group optionally substituted by 1 to 3 substituents selected from (i) Ci_6 alkyl optionally substituted by 1 to 3 halogen atoms and (ii) Ci_6 alkoxy optionally substituted by 1 to 3 halogen atoms, R2 is a phenyl group optionally substituted by 1 to 5 substituents selected from 15 (i) a halogen atom and (ii) Ci_6 alkyl optionally substituted by
    1 to 3 halogen atoms, R3 and R4 are each a hydrogen atom, and R5 is methyl.
    9915521_1 (GHMatters) P76750.AU.2
    259
AU2015268744A 2005-08-30 2015-12-15 1-Heterocyclylsulfonyl, 3-aminomethyl, 5-(hetero-)aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors Active AU2015268744B2 (en)

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WO2006036024A1 (en) * 2004-09-30 2006-04-06 Takeda Pharmaceutical Company Limited Proton pump inhibitors

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WO2006036024A1 (en) * 2004-09-30 2006-04-06 Takeda Pharmaceutical Company Limited Proton pump inhibitors

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