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

• US 10,548,899 B2
• Filed: 10/19/2016
• Issued: 02/04/2020
• Est. Priority Date: 10/20/2015
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• 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
• Primary Examiner(s): Rodriguez-Garcia, Valerie
• Application Number:
  US15/769,295
• Publication Number:
  US 20180303841A1
• Time in Patent Office: 1,203 Days
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/53 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 Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 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 Class Codes: C07D 239/88 Oxygen atoms
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

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.

Claims

1. A compound represented by the formula:

2. The compound according to claim 1, wherein

R¹ is a hydrogen atom, a halogen atom, a C_1-6 alkyl group or a C_1-6 alkoxy group;

R² is a hydrogen atom, a halogen atom, a C_1-6 alkyl group or a C_1-6 alkoxy group;

when one of R¹ and R² is a hydrogen atom, then the other is other than a hydrogen atom;

R³ 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

R¹ is a hydrogen atom, a halogen atom or a C_1-6 alkyl group;

R² is a C_1-6 alkyl group;

R³ 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

R¹ is a halogen atom or a C_1-6 alkyl group;

R² is a C_1-6 alkyl group;

R³ 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.

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

R³ 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 substituted by 1 to 3 C_1-6 alkyl groups,

or a salt thereof.

11. The compound according to claim 3, wherein

R³ 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, or

(3) a C_3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups;

and

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 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 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.