Heterocyclic compound

Patent metadata

Field	Value
Publication number	US-2022017514-A1
Application number	US-201917413473-A
Country	US
Kind code	A1
Filing date	Dec 11, 2019
Priority date	Dec 12, 2018
Publication date	Jan 20, 2022
Grant date	—

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 description, or a salt thereof has an orexin type 2 receptor agonist activity, and is useful as an agent for the prophylaxis or treatment of narcolepsy.

First claim

1 . A compound represented by the formula:

wherein
R 1 is an optionally substituted C 1-6 alkylsulfonyl group, an optionally substituted mono- or di-C 1-6 alkylaminosulfonyl group, an optionally substituted 3- to 6-membered cyclylsulfonyl group, a formylcarbonyl group, a carboxycarbonyl group, a carbamoylcarbonyl group, an optionally substituted C 1-6 alkyl-carbonyl group, an optionally substituted C 1-6 alkoxy-carbonyl group, an optionally substituted mono- or di-C 1-6 alkyl-carbamoyl group, an optionally substituted C 1-6 alkyl-carbonyl-carbonyl group, an optionally substituted C 1-6 alkoxy-carbonyl-carbonyl group, an optionally substituted mono- or di-C 1-6 alkyl-carbamoyl-carbonyl group or an optionally substituted 3- to 6-membered cyclylcarbonyl group;
R 2 and R 3 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group or a halogen atom;
X is an optionally substituted methylene group or an oxygen atom;
Y and Z are each independently a carbon atom or a nitrogen atom;
Ring A is an optionally substituted 5- or 6-membered nitrogen-containing aromatic heterocycle;
L is an optionally substituted methylene group, an oxygen atom, —O-L 1 -, -L 1 -O— or -L 1 -L 2 -;
L 1 and L 2 are each independently an optionally substituted methylene group; and
Ring B is an optionally further substituted 4- to 7-membered ring,
or a salt thereof.

2 . The compound or salt according to claim 1 ,
wherein R 1 is, (1) a C 1-6 alkylsulfonyl group, (2) a mono- or di-C 1-6 alkyl-carbamoyl-carbonyl group, or (3) a 3- to 6-membered non-aromatic heterocyclylcarbonyl group; R 2 and R 3 are both hydrogen atoms; X is a methylene group; Y and Z are each independently a carbon atom or a nitrogen atom; Ring A is a 5- or 6-membered aromatic heterocycle optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a C 1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, and
(d) a mono- or di-C 1-6 alkyl-carbamoyl group;
L is a methylene group or —O—CH 2 —; and Ring B is a 6-membered ring further substituted by 1 to 3 substituents selected from
(a) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom, and
(ii) a C 1-6 alkyl group, and

(b) a 5- or 6-membered monocyclic aromatic heterocyclic group or a 8- to 14-membered fused polycyclic aromatic heterocyclic group, each optionally substituted 1 to 3 substituents selected from
(i) a halogen atom,
(ii) a C 1-6 alkyl group, and
(iii) a C 1-6 alkoxy group.

3 . The compound or salt according to claim 1 , wherein
R 2 is, (1) a C 1-6 alkylsulfonyl group, (2) a mono- or di-C 1-6 alkyl-carbamoyl-carbonyl group, or (3) a tetrahydrofurylcarbonyl group; R 2 and R 3 are both hydrogen atoms; X is a methylene group; Y and Z are each independently a carbon atom or a nitrogen atom; Ring A is (1) a pyrazole ring optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a C 1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, and
(d) a mono- or di-C 1-6 alkyl-carbamoyl group,
(2) a triazole ring optionally substituted by 1 to 3 C 1-6 alkyl groups, (3) an imidazole ring optionally substituted by 1 to 3 C 1-6 alkyl groups, (4) a triazole ring optionally substituted by 1 to 3 C 1-6 alkyl groups, or (5) a pyridine ring optionally substituted by 1 to 3 C 1-6 alkyl groups; L is a methylene group or —O—CH 2 —; and Ring B is (1) a cyclohexane ring further substituted by 1 to 3 C 6-14 aryl groups, (2) a piperidine ring further substituted by 1 to 3 substituents selected from
(a) a C 6-14 aryl group optionally substituted by 1 to 3 halogen atoms, and
(b) a pyridyl group, a pyrimidinyl group or a quinazolinyl group, each optionally substituted 1 to 3 substituents selected from
(i) a halogen atom,
(ii) a C 1-6 alkyl group, and
(iii) a C 1-6 alkoxy group,

(3) a benzene ring further substituted by 1 to 3 substituents selected from
(a) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom, and
(ii) a C 1-6 alkyl group, and

(b) a pyridyl group optionally substituted by 1 to 3 C 1-6 alkyl groups, or
(4) a pyridine ring further substituted by 1 to 3 C 6-14 aryl groups optionally substituted by 1 to 3 halogen atoms.

4 . The compound or salt according to claim 1 , wherein
R 2 is a C 1-6 alkylsulfonyl group; R 2 and R 3 are both hydrogen atoms; X is a methylene group; Y and Z are each independently a carbon atom or a nitrogen atom; Ring A is a pyrazole ring optionally substituted by 1 to 3 C 1-6 alkyl groups; L is —O—CH 2 —; and Ring B is a piperidine ring further substituted by 1 to 3 pyrimidinyl groups optionally substituted by 1 to 3 halogen atoms.

5 . The compound of claim 1 , which is N-[7-({[1-(5-Fluoropyrimidin-2-yl)piperidin-4-yl]oxy}methyl)-2-(propan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-6-yl]methanesulfonamide or a salt thereof.

6 . The compound of claim 1 , which is N-[2-Ethyl-7-({[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]oxy}methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-6-yl]methanesulfonamide or a salt thereof.

7 . The compound of claim 1 , which is N-[2-(Propan-2-yl)-7-({[1-(pyrimidin-2-yl)piperidin-4-yl]oxy}methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-6-yl]methanesulfonamide or a salt thereof.

8 . A medicament comprising the compound or salt according to claim 1 .

9 . The medicament according to claim 8 , which is an orexin type 2 receptor agonist.

10 . The medicament according to claim 8 , which is an agent for the prophylaxis or treatment of narcolepsy.

11 . The compound or salt according to claim 1 for use in the prophylaxis or treatment of narcolepsy.

12 . A method for activating an orexin type 2 receptor in a mammal, which comprises administering an effective amount of the compound or salt according to claim 1 to the mammal.

13 . A method for preventing or treating narcolepsy in a mammal, which comprises administering an effective amount of the compound or salt according to claim 1 to the mammal.

14 . (canceled)

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Kajita Yuichi
• Miyanohana Yuhei
• Koike Tatsuki
• Hoashi Yasutaka
• Hattori Yasushi
• Tokunaga Norihito
• Oda Tsuneo
• Miyazaki Tohru
• Uyghur Dilhumar
• Ito Yoshiteru
• Takeuchi Kohei
• Imamura Keisuke
• Sugimoto Takahiro
• Fukuda Koichiro
• Kohara Yasuhisa
• Okamoto Rei
• Ohra Taiichi
• Miyamoto Naoki
• Terao Yoshito
• Kawasaki Masanori

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D231/54

  condensed with carbocyclic rings or ring systems · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D277/64

  with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 · CPC title