Granted Patent B2

US 12,637,418 · App. 17/310,164 · Granted May 26, 2026

Inventors: Yuya Oguro (Kanagawa, JP); Makoto Kamata (Kanagawa, JP); Satoshi Mikami (Kanagawa, JP); Shinji Morimoto (Kanagawa, JP); Sachie Takashima (Kanagawa, JP); Masaki Daini (Kanagawa, JP); Osamu Kubo (Kanagawa, JP); Fumiaki Kikuchi (Kanagawa, JP); Akinori Toita (Kanagawa, JP); Florian Puenner (Kanagawa, JP); Takahito Kasahara (Kanagawa, JP); Masataka Murakami (Kanagawa, JP); Shuhei Ikeda (Kanagawa, JP); Fumie Yamaguchi (Kanagawa, JP); Minoru Nakamura (Kanagawa, JP); Takafumi Yukawa (Kanagawa, JP)

Assignee: Takeda Pharmaceutical Company Limited

C07C255/60A61P25/06A61P25/24A61P25/28A61P29/00C07D213/82C07D401/12C07D409/12

Abstract

Claims (149)

1 . A compound represented by the formula (I):

wherein

ring A is a 6-membered aromatic ring substituted by a —CN group and a

 group, wherein the —CN group is meta relative to the

 group;

ring A is further substituted by 1 to 4 substituents selected from

(1) a C 1-3 alkyl group,

(2) a C 1-3 haloalkyl group,

(3) an optionally substituted cyclic group,

(4) an optionally substituted C 1-6 alkoxy group, and

(5) a halogen atom;

R 1 and R 2 are each independently a hydrogen atom or a C 1-3 alkyl group optionally substituted by fluorine atom(s);

R 3 is

(1) a group represented by

wherein

R 4 is a substituent selected from

(1) a C 1-3 haloalkyl group,

(2) an optionally substituted C 3-7 cycloalkyl group, and

(3) an optionally substituted C 1-6 alkoxy group,

Y is a nitrogen atom or CR 6 ,

R 6 is a hydrogen atom or a halogen atom, and

Z is a hydrogen atom or a halogen atom, or

(2) a group represented by

wherein

R 5 is a substituent selected from

(1) a C 1-3 haloalkyl group,

(2) an optionally substituted C 3-7 cycloalkyl group, and

(3) an optionally substituted C 1-6 alkoxy group, and

ring B is a thiophene ring optionally further substituted by one halogen atom, or a salt thereof.

2 . The compound according to claim 1 , wherein

ring A is a 6-membered aromatic ring further substituted by 1 or 2 substituents selected from

(1) a C 1-3 alkyl group,

(2) a C 3-10 cycloalkyl group,

(3) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, and

(4) a halogen atom;

R 1 and R 2 are each a hydrogen atom;

R 3 is

(1) a group represented by

wherein

R 4 is a C 1-3 haloalkyl group or a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms,

Y is a nitrogen atom or CR 6 ,

R 6 is a hydrogen atom,

Z is a halogen atom or a hydrogen atom; or

(2) a group represented by

wherein

R 5 is a C 1-3 haloalkyl group, and

ring B is a thiophene ring optionally further substituted by one halogen atom;

or a salt thereof.

3 . N-[(5-cyano-2-methoxypyridin-3-yl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide or a salt thereof.

4 . N-[(3-cyano-2-fluoro-6-methoxyphenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide or a salt thereof.

5 . A medicament comprising the compound according to claim 1 or a salt thereof.

6 . The compound according to claim 1 or a salt thereof, wherein:

R 1 and R 2 are each a hydrogen atom.

7 . The compound according to claim 1 or a salt thereof, wherein:

R 3 is a group represented by:

R 4 is a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;

Y is a nitrogen atom; and

Z is a halogen atom.

8 . The compound according to claim 1 or a salt thereof, wherein:

R 3 is a group represented by:

R 4 is a C 1-3 haloalkyl group or a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;

Y is CR 6 ; and

one of R 6 and Z is a halogen atom and the other is a hydrogen atom.

9 . The compound according to claim 1 or a salt thereof, wherein:

ring A is a 6-membered aromatic ring further substituted by 1 or 2 substituents selected from

(1) a C 1-3 alkyl group,

(2) a C 3-10 cycloalkyl group,

(3) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, and

(4) a halogen atom;

R 1 and R 2 are each a hydrogen atom;

R 3 is a group represented by:

R 4 is a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;

Y is a nitrogen atom; and

Z is a halogen atom.

10 . The compound according to claim 9 or a salt thereof, wherein:

ring A is a benzene ring or pyridine ring, further substituted by 1 or 2 substituents selected from

(1) methyl,

(2) cyclopropyl,

(3) methoxy or ethoxy, optionally substituted by 1 to 3 fluorine atoms, and

(4) a fluorine atom or bromine atom;

R 1 and R 2 are each a hydrogen atom;

R 3 is a group represented by:

R 4 is methoxy optionally substituted by 1 to 3 fluorine atoms;

Y is a nitrogen atom; and

Z is a fluorine atom.

11 . The compound according to claim 1 or a salt thereof, wherein:

ring A is a 6-membered aromatic ring further substituted by 1 or 2 substituents selected from

(1) a C 1-3 alkyl group,

(2) a C 3-10 cycloalkyl group,

(3) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, and

(4) a halogen atom;

R 1 and R 2 are each a hydrogen atom;

R 3 is a group represented by:

R 4 is a C 1-3 haloalkyl group or a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;

Y is CR 6 ;

R 6 is a hydrogen atom; and

Z is a hydrogen atom or a halogen atom.

12 . The compound according to claim 11 or a salt thereof, wherein:

ring A is a benzene ring or pyridine ring, further substituted by 1 or 2 substituents selected from

(1) methyl,

(2) cyclopropyl,

(3) methoxy or ethoxy, optionally substituted by 1 to 3 fluorine atoms, and

(4) a fluorine atom or bromine atom;

R 1 and R 2 are each a hydrogen atom;

R 3 is a group represented by:

R 4 is trifluoromethyl or methoxy optionally substituted by 1 to 3 fluorine atoms;

Y is CR 6 ;

R 6 is a hydrogen atom; and

Z is a hydrogen atom or a fluorine atom.

13 . The compound according to claim 1 or a salt thereof, wherein:

ring A is a benzene ring or a pyridine ring, further substituted by 1 or 2 substituents selected from methoxy and a fluorine atom;

R 1 and R 2 are each a hydrogen atom;

R 3 is a group represented by:

R 4 is methoxy optionally substituted by 1 to 3 fluorine atoms;

Y is a nitrogen atom; and

Z is a fluorine atom.

14 . The compound according to claim 1 or a salt thereof, wherein the compound is selected from

N-[(2-bromo-5-cyanophenyl)methyl]-3-fluoro-4-(trifluoromethoxy)benzamide,

N-[(2-bromo-5-cyanophenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(2-bromo-5-cyanophenyl)methyl]-4-(difluoromethoxy)-3-fluorobenzamide,

N-[(5-cyano-2-cyclopropylphenyl)methyl]-3-fluoro-4-(trifluoromethoxy)benzamide,

N-[(5-cyano-2-cyclopropylphenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(5-cyano-2-cyclopropylphenyl)methyl]-4-(difluoromethoxy)-3-fluorobenzamide,

N-[(5-cyano-2-methoxyphenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(5-cyano-2-methylphenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(5-cyano-2-methoxypyridin-3-yl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(5-cyano-2-methoxyphenyl)methyl]-4-(difluoromethoxy)-3-fluorobenzamide,

N-[(5-cyano-2-methoxyphenyl)methyl]-3-fluoro-4-(trifluoromethoxy)benzamide,

N-[(5-cyano-2-fluorophenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-{[5-cyano-2-(2,2,2-trifluoroethoxy)phenyl]methyl}-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-{[5-cyano-2-(2,2-difluoroethoxy)phenyl]methyl}-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(3-cyano-6-fluoro-2-methoxyphenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(5-cyano-2-methoxypyridin-3-yl)methyl]-5-(trifluoromethyl)thiophene-2-carboxamide,

N-[(3-cyano-2-fluoro-6-methoxyphenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(3-cyano-6-fluoro-2-methylphenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(6-cyano-3-methoxypyridin-2-yl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(5-cyano-3-fluoro-2-methoxyphenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(5-cyano-3-fluoro-2-methoxyphenyl)-methyl]-5-fluoro-6-methoxypyridine-3-carboxamide,

N-[(2-cyano-3-fluoro-5-methoxypyridin-4-yl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(5-cyano-4-fluoro-2-methoxyphenyl)-methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(3-cyano-5-methoxyphenyl)-methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(5-cyano-2-fluoro-3-methoxyphenyl)-methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(5-cyano-2-fluoro-3-methoxyphenyl)-methyl]-5-fluoro-6-methoxypyridine-3-carboxamide,

N-[(6-cyano-3-methoxy-2-methylpyridin-4-yl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(2-cyano-5-methoxypyridin-4-yl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide,

N-[(2-cyano-5-methoxypyridin-4-yl)methyl]-4-(trifluoromethoxy)bezamide, and

N-[(2-cyano-5-methoxypyridin-4-yl)methyl]-3-fluoro-4-(trifluoromethyl)bezamide.

15 . A method for antagonizing an NMDA receptor containing an NR2B subunit in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

16 . A method for treating depression, bipolar disorder, migraine, pain, or peripheral symptoms of dementia in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

Assignments (1)

Priority Claims (1)

Continuity (1)

References Cited (148)