Granted Patent B2

US 12,378,256 · App. 17/475,733 · Granted Aug 5, 2025

Inventors: Kazuaki Takami (Kanagawa, JP); Masaki Seto (Kanagawa, JP); Shinobu Sasaki (Kanagawa, JP); Haruhi Ando (Tokyo, JP); Masaki Ogino (Kanagawa, JP); Tomoko Ohashi (Kanagawa, JP); Toshihiro Imaeda (Kanagawa, JP); Ikuo Fujimori (Tokyo, JP); Yasuhiro Tsukimi (Kanagawa, JP); Masami Yamada (Kanagawa, JP); Kenichiro Shimokawa (Kanagawa, JP); Takeshi Wakabayashi (Kanagawa, JP); Masataka Murakami (Kanagawa, JP); Makoto Fushimi (New York, NY); Tomohiro Okawa (Kanagawa, JP); Jinichi Yonemori (Kanagawa, JP); Tomohiro Ohashi (Kanagawa, JP); Hideo Suzuki (Kanagawa, JP); Hironobu Maezaki (Kanagawa, JP); Ayumu Sato (Kanagawa, JP); Yasutomi Asano (Kanagawa, JP); Steve Swann (San Diego, CA)

Assignee: Takeda Pharmaceutical Company Limited

C07D491/048A61K31/4355A61P1/10

Abstract

Claims (104)

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

wherein

R 1 is an optionally substituted cyclic group;

R 2 is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group;

is a single bond or a double bond;

ring A is a benzene ring substituted by (a) one halogen atom and (b) one mono- or di-C 1-6 alkyl-carbamoyl group optionally substituted by 1 or 2 substituents selected from (i) a C 1-6 alkoxy group, (ii) a C 3-10 cycloalkyl group, (iii) a 3- to 14-membered non-aromatic heterocyclic group, (iv) a C 6-14 aryl group optionally substituted by 1 to 3 hydroxy groups, (v) a C 1-6 alkoxy-carbonyl group, (vi) a carboxy group, (vii) a C 1-6 alkylthio group, (viii) a mono- or di-C 1-6 alkyl-carbamoyl group, and (ix) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group; and

R 3 and R 4 are each independently a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group,

or a salt thereof.

2. The compound according to claim 1 , wherein

R 1 is

(1) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group, or

(2) an optionally substituted C 3-10 cycloalkyl group;

R 2 is a hydrogen atom or an optionally substituted C 1-6 alkyl group; and

R 3 and R 4 are each independently a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group,

or a salt thereof.

3. The compound according to claim 1 , wherein

R 1 is

(1) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups, or

(2) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom;

R 2 is a hydrogen atom or a C 1-6 alkyl group; and

R 3 and R 4 are each independently a hydrogen atom, a halogen atom or a C 1-6 alkyl group,

or a salt thereof.

4. The compound according to claim 3 , wherein

R is

or a salt thereof.

5. The compound according to claim 3 , wherein

ring A is

a benzene ring substituted by (a) one halogen atom and (b) one mono- or di-C 1-6 alkyl-carbamoyl group optionally substituted by 1 or 2 substituents selected from (i) a C 1-6 alkoxy group and (ii) a 3- to 14-membered non-aromatic heterocyclic group,

or a salt thereof.

6. The compound according to claim 1 , wherein

R 1 is a 3- to 14-membered non-aromatic heterocyclic group substituted by one hydroxy group;

R 2 is a hydrogen atom;

ring A is

a benzene ring substituted by (a) one halogen atom and (b) one mono- or di-C 1-6 alkyl-carbamoyl group optionally substituted by 1 or 2 substituents selected from (i) a C 1-6 alkoxy group and (ii) a 3- to 14-membered non-aromatic heterocyclic group; and

R 3 and R 4 are each independently a hydrogen atom or a halogen atom,

or a salt thereof.

7. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof and a pharmaceutically acceptable carrier.

8. A method of cholinergic muscarinic M1 receptor positive allosteric modulation in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to said mammal.

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

wherein:

R 1 is

(1) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups, or

(2) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom;

R 2 is a hydrogen atom or a C 1-6 alkyl group;

is a single bond or a double bond;

ring A is

wherein R 5A is a mono- or di-C 1-6 alkyl-carbamoyl group optionally substituted by 1 or 2 substituents selected from a C 1-6 alkoxy group and a 3- to 14-membered non-aromatic heterocyclic group;

X is CR 6A ; and

R 6A is a hydrogen atom or a halogen atom; and

R 3 and R 4 are each independently a hydrogen atom, a halogen atom or a C 1-6 alkyl group,

or a salt thereof.

10. A method for the treatment of constipation in a mammal, comprising administering an effective amount of a compound represented by the formula (I):

wherein

R 1 is an optionally substituted cyclic group;

R 2 is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group;

is a single bond or a double bond;

ring A is an optionally substituted ring; and

R 3 and R 4 are each independently a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group,

or a salt thereof to the mammal.

11. The method according to claim 10 , wherein

R 1 is

(1) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group, or

(2) an optionally substituted C 3-10 cycloalkyl group;

R 2 is a hydrogen atom or an optionally substituted C 1-6 alkyl group;

ring A is

(1) an optionally substituted benzene ring,

(2) an optionally substituted 5- or 6-membered monocyclic aromatic heterocycle,

(3) an optionally substituted 4- to 6-membered monocyclic non-aromatic heterocycle, or

(4) an optionally substituted 9- to 14-membered fused polycyclic non-aromatic heterocycle; and

R 3 and R 4 are each independently a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group.

12. The method according to claim 10 , wherein

R 1 is

(1) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups, or

(2) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom;

R 2 is a hydrogen atom or a C 1-6 alkyl group;

ring A is

(1) a benzene ring optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, (b) a C 1-6 alkoxy group, (c) a mono- or di-C 1-6 alkyl-carbamoyl group optionally substituted by 1 or 2 substituents selected from (i) a C 1-6 alkoxy group, (ii) a C 3-10 cycloalkyl group, (iii) a 3- to 14-membered non-aromatic heterocyclic group, (iv) a C 6-14 aryl group optionally substituted by 1 to 3 hydroxy groups, (v) a C 1-6 alkoxy-carbonyl group, (vi) a carboxy group, (vii) a C 1-6 alkylthio group, (viii) a mono- or di-C 1-6 alkyl-carbamoyl group, and (ix) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, (d) a mono- or di-C 3-10 cycloalkyl-carbamoyl group, (e) a C 6-14 aryl-carbamoyl group optionally substituted by 1 to 3 hydroxy groups, and (f) a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups,

(2) a 5- or 6-membered monocyclic aromatic heterocycle optionally substituted by 1 to 3 substituents selected from (a) a C 1-6 alkoxy group and (b) a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups,

(3) a 4- to 6-membered monocyclic non-aromatic heterocycle optionally substituted by one oxo group, or

(4) a 9- to 14-membered fused polycyclic non-aromatic heterocycle optionally substituted by 1 to 3 substituents selected from a C 1-6 alkyl group and an oxo group; and

R 3 and R 4 are each independently a hydrogen atom, a halogen atom or a C 1-6 alkyl group.

13. The method according to claim 12 , wherein

R 1 is

14. The method according to claim 12 , wherein

ring A is

(1) a benzene ring substituted by 1 to 3 substituents selected from (a) a halogen atom, (b) a mono- or di-C 1-6 alkyl-carbamoyl group optionally substituted by 1 or 2 substituents selected from (i) a C 1-6 alkoxy group and (ii) a 3- to 14-membered non-aromatic heterocyclic group, and (c) a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups, or

(2) a 5- or 6-membered monocyclic aromatic heterocycle substituted by one 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups.

15. The method according to claim 12 , wherein

ring A is

wherein R 5A is a mono- or di-C 1-6 alkyl-carbamoyl group optionally substituted by 1 or 2 substituents selected from a C 1-6 alkoxy group and a 3- to 14-membered non-aromatic heterocyclic group;

X is CR 6A ; and

R 6A is a hydrogen atom or a halogen atom.

16. The method according to claim 12 , wherein

ring A is

wherein R 5A is a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups;

X is CR 6A or N; and

R 6A is a hydrogen atom or a halogen atom.

17. The method according to claim 10 , wherein

R 1 is a 3- to 14-membered non-aromatic heterocyclic group substituted by one hydroxy group;

R 2 is a hydrogen atom;

ring A is

(1) a benzene ring substituted by 1 to 3 substituents selected from (a) a halogen atom, (b) a mono- or di-C 1-6 alkyl-carbamoyl group optionally substituted by 1 or 2 substituents selected from (i) a C 1-6 alkoxy group and (ii) a 3- to 14-membered non-aromatic heterocyclic group, and (c) a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups, or

(2) a 5- or 6-membered monocyclic aromatic heterocycle substituted by one 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups; and

R 3 and R 4 are each independently a hydrogen atom or a halogen atom.

Priority Claims (2)

Continuity (3)

References Cited (81)