Quinazolinone and benzotriazinone compounds with cholinergic muscarinin M1 receptor positive allosteric modulator activity

Patent metadata

Field	Value
Publication number	US-10548899-B2
Application number	US-201615769295-A
Country	US
Kind code	B2
Filing date	Oct 19, 2016
Priority date	Oct 20, 2015
Publication date	Feb 4, 2020
Grant date	Feb 4, 2020

Abstract

The present invention provides a compound which has a cholinergic muscarinic M1 receptor positive allosteric modulator activity and may be useful as a medicament such as an agent for the prophylaxis or treatment of Alzheimer's disease, schizophrenia, pain, sleep disorder, Parkinson's disease dementia, Lewy body dementia and the like. The present invention relates to a compound represented by the formula (I) or a salt thereof. In the formula (I), each symbol is as described in the attached specification.

First claim

The invention claimed is:

1. A compound represented by the formula:

wherein
R 1 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
R 2 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
R 3 is

(1) a hydrogen atom,
(2) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from 3- to 14-membered non-aromatic heterocyclic groups,
(3) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups,
(4) a 5- to 14-membered aromatic heterocyclic group optionally substituted 1 to 3 cyano groups,
(5) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups, or
(6) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom, and
(b) a cyano group;
ring A is

(1) a benzene ring optionally further substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a C 1-6 alkoxy group optionally substituted by 1 to 5 halogen atoms, and
(d) 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 further substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a C 1-6 alkyl group, and
(c) a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups, or

(3) a 4- to 6-membered monocyclic non-aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from
(a) a cyano group, and
(b) a 5- to 14-membered aromatic heterocyclic group; and
X is CH or N,

or a salt thereof.

2. The compound according to claim 1 , wherein
R 1 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
R 2 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
when one of R 1 and R 2 is a hydrogen atom, then the other is other than a hydrogen atom;
R 3 is

(1) a hydrogen atom,
(2) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from 3- to 14-membered non-aromatic heterocyclic groups,
(3) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups,
(4) a 5- to 14-membered aromatic heterocyclic group optionally substituted 1 to 3 cyano groups,
(5) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups, or
(6) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom, and
(b) a cyano group;
ring A is

(1) a benzene ring optionally further substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a C 1-6 alkoxy group optionally substituted by 1 to 5 halogen atoms, and
(d) 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 further substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a C 1-6 alkyl group, and
(c) a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups, or

(3) a 4- to 6-membered monocyclic non-aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from
(a) a cyano group, and
(b) a 5- to 14-membered aromatic heterocyclic group; and
X is CH or N,

or a salt thereof.

3. The compound according to claim 1 , wherein
R 1 is a hydrogen atom, a halogen atom or a C 1-6 alkyl group;
R 2 is a C 1-6 alkyl group;
R 3 is

(1) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from 3- to 14-membered non-aromatic heterocyclic groups,
(2) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups, or
(3) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups;
ring A is

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

(3) a 4- to 6-membered monocyclic non-aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from
(a) a cyano group, and
(b) a 5- to 14-membered aromatic heterocyclic group; and
X is CH or N,

or a salt thereof.

4. The compound according to claim 1 , wherein
R 1 is a halogen atom or a C 1-6 alkyl group;
R 2 is a C 1-6 alkyl group;
R 3 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 hydroxy groups;
ring A is

(1) a benzene ring optionally further substituted by 1 to 3, 5- to 14-membered aromatic heterocyclic groups optionally substituted by 1 to 3 C 1-6 alkyl groups, or
(2) a 5- or 6-membered monocyclic aromatic heterocycle optionally further substituted by 1 to 3, 5- to 14-membered aromatic heterocyclic groups optionally substituted by 1 to 3 C 1-6 alkyl groups; and
X is CH or N,

or a salt thereof.

5. 8-Fluoro-3-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-7-methyl-6-(4-(1H-pyrazol-1-yl)benzyl)quinazolin-4(3H)-one, or a salt thereof.

6. 3-((3S,4S)-4-Hydroxytetrahydro-2H-pyran-3-yl)-7,8-dimethyl-6-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-1,2,3-benzotriazin-4(3H)-one, or a salt thereof.

7. 3-((1S,2S)-2-Hydroxycyclohexyl)-7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one, or a salt thereof.

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

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

10. The compound according to claim 2 , wherein
R 3 is

(1) a C 1-6 alkyl group substituted by 1 to 3 substituents selected from 3- to 14-membered non-aromatic heterocyclic groups,
(2) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups,
(3) a 5- to 14-membered aromatic heterocyclic group optionally substituted 1 to 3 cyano groups,
(4) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups, or
(5) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom, and
(b) a cyano group; and
ring A is

(1) a benzene ring optionally further optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a C 1-6 alkoxy group optionally substituted by 1 to 5 halogen atoms, and
(d) 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 optionally further substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a C 1-6 alkyl group, and
(c) a 5- to 14-membered aromatic heterocyclic group optionally substitut

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Sugimoto Takahiro
• Suzuki Shinkichi
• Sakamoto Hiroki
• Yamada Masami
• Nakamura Minoru
• Kamata Makoto
• Shimokawa Kenichiro
• Ogino Masaki
• Kimura Eiji
• Murakami Masataka
• Kojima Takuto
• Yonemori Jinichi

Classifications

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/53 Primary

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title