Pyrrolo[1, 2-c]imidazole derivatives as orexin type 2 receptor agonists and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12534471-B2
Application number	US-202418629703-A
Country	US
Kind code	B2
Filing date	Apr 8, 2024
Priority date	Oct 31, 2022
Publication date	Jan 27, 2026
Grant date	Jan 27, 2026

Abstract

The present invention provides a heterocyclic compound having an orexin type 2 receptor agonist activity.
A compound represented by the formula (I):

wherein each symbol is as described in the specification, or a salt thereof, is useful as an agent for the prophylaxis or treatment of narcolepsy.

First claim

The invention claimed is:

1 . A method for the prophylaxis or treatment of a disease or disorder associated with an orexin type 2 receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound represented by the formula (Ia):

wherein
R 1 is a C 1-6 alkyl group, a C 3-10 cycloalkyl group, or a mono-C 1-6 alkylamino group;
r is 0 or 1;
R 2 and R 3 are each independently a hydrogen atom, or
when r is 0, then R 2 and R 3 may be taken together to form a bond;
R 4 is a hydrogen atom;
R 5 is a phenyl group optionally substituted by 1 to 3 halogen atoms;
R 6 and R 7 are each independently a hydrogen atom, or a halogen atom;
X 5 is CH or N; and
R 12 and R 13 are each independently a hydrogen atom, a C 1-6 alkyl group, or a halogen atom;
or a salt thereof.

2 . The method according to claim 1 , wherein the disease or disorder is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer's disease, obesity, insulin resistance syndrome, disturbance of consciousness, and side effects and complications due to anesthesia.

3 . The method according to claim 1 , wherein the disease or disorder is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

4 . The method according to claim 1 , wherein the disease or disorder is narcolepsy.

5 . The method according to claim 1 , wherein
R 1 is a C 1-6 alkyl group; r is 0 or 1; R 2 and R 3 are each a hydrogen atom, or when r is 0, then R 2 and R 3 may be taken together to form a bond; R 4 is a hydrogen atom; R 5 is a phenyl group substituted by 1 to 3 halogen atoms; R 6 and R 7 are each a halogen atom; X 5 is CH; and R 12 and R 13 are each independently a hydrogen atom, or a halogen atom; or a salt thereof.

6 . The method according to claim 1 , wherein the compound is selected from the group consisting of:
N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; N-{(4aR,6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; and N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; or a salt thereof.

7 . The method according to claim 1 , wherein the compound is selected from the group consisting of:
N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; and N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; or a salt thereof.

8 . The method according to claim 1 , wherein the compound is selected from the group consisting of:
N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; and N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; or a salt thereof.

9 . The method according to claim 1 , wherein the compound is selected from the group consisting of:
N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; N-{(4aR,6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; and N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; or a salt thereof.

10 . A method for treating a subject having one or more central disorders of hypersomnolence (CDH), the method comprising administering to the subject a compound represented by the formula (Ia):

wherein
R 1 is a C 1-6 alkyl group, a C 3-10 cycloalkyl group, or a mono-C 1-6 alkylamino group;
r is 0 or 1;
R 2 and R 3 are each independently a hydrogen atom, or
when r is 0, then R 2 and R 3 may be taken together each other to form a bond;
R 4 is a hydrogen atom;
R 5 is a phenyl group optionally substituted by 1 to 3 halogen atoms;
R 6 and R 7 are each independently a hydrogen atom, or a halogen atom;
X 5 is CH or N; and
R 12 and R 13 are each independently a hydrogen atom, a C 1-6 alkyl group, or a halogen atom;
or a salt thereof.

11 . The method according to claim 10 , wherein
R 1 is a C 1-6 alkyl group; r is 0 or 1; R 2 and R 3 are each a hydrogen atom, or when r is 0, then R 2 and R 3 may be taken together to form a bond; R 4 is a hydrogen atom; R 5 is a phenyl group substituted by 1 to 3 halogen atoms; R 6 and R 7 are each a halogen atom; X 5 is CH; and R 12 and R 13 are each independently a hydrogen atom, or a halogen atom; or a salt thereof.

12 . The method according to claim 10 , wherein the compound is selected from the group consisting of:
N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluo

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Hattori Yasushi
• Pira Marilena
• Ito Yoshiteru
• Takeuchi Kohei
• Kimura Eiji
• Tokunaga Norihito
• Ikeda Shuhei
• Pawliczek Martin Alexander
• Tezuka Noriyuki
• Hoashi Yasutaka
• Miyanohana Yuhei
• Kajita Yuichi
• Koike Tatsuki

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title