Bicyclic heterocyclic compound containing a substituted pyrrole ring

Patent metadata

Field	Value
Publication number	US-9777005-B2
Application number	US-201314443598-A
Country	US
Kind code	B2
Filing date	Nov 18, 2013
Priority date	Nov 19, 2012
Publication date	Oct 3, 2017
Grant date	Oct 3, 2017

Abstract

Provided is a compound having a cholinergic muscarinic M1 receptor positive allosteric modulator activity, and useful as a prophylactic or therapeutic drug for Alzheimer's disease, schizophrenia, pain, sleep disorder and the like. The present invention relates to a compound represented by the formula

wherein ring A is a 4- to 7-membered ring optionally having substituent(s); L is —O—, —S—, —SO— or —SO 2 —; R 1 is a C 1-6 alkyl group optionally having substituent(s) (provided that when L is —O—, R 1 is not a C 1-6 alkyl group optionally substituted by halogen atom(s)), or a cyclic group optionally having substituent(s); X 1 is —CRa═ or —N═; X 2 is —CRb═ or —N═; X 3 is —CRc= or —N═; Ra, Rb and Rc are each a C 1-6 alkyl group, C 2-6 alkenyl group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, C 3-6 cycloalkoxy group or C 6-14 aryl group, each of which optionally having substituent(s), H or halogen, or a salt thereof.

First claim

The invention claimed is:

1. A compound represented by formula (1)

wherein
ring A is a benzene ring, a C 4-7 cycloalkane ring, a pyridine ring, a thiophene ring, a furan ring, or a piperidine ring, each of which is optionally substituted by from 1 to 3 substituents selected from the group consisting of
(1) a halogen atom,
(2) a cyano group,
(3) a carbamoyl group optionally mono-substituted by a C 1-6 alkyl group optionally substituted by from 1 to 3 tetrahydrofuryl groups,
(4) a C 1-6 alkoxy-carbonyl group,
(5) a C 3-6 cycloalkyl group, and
(6) a pyrazolyl group, a piperidyl group, a pyridyl group, a pyridazinyl group, a triazolyl group, an imidazolyl group, an isoxazolyl group, a pyrazolopyridyl group, or a 4,5,6,7-tetrahydropyrazolopyridyl group, each of which optionally has from 1 to 3 substituents selected from the group consisting of
(i) a halogen atom,
(ii) a C 1-6 alkyl group optionally substituted by from 1 to 3 substituents selected from the group consisting of a halogen atom and a C 3-6 cycloalkyl group, and
(iii) a tetrahydropyranyl group;

L is —O—,
R 1 is
(I) a C 3-8 cycloalkyl group, a phenyl group, a pyridyl group, a tetrahydropyranyl group, a 6,7-dihydro-5H-cyclopentapyridyl group, or a pyrazolyl group, each of which is optionally substituted by from 1 to 3 substituents selected from the group consisting of
(1) a halogen atom,
(2) a cyano group,
(3) a nitro group,
(4) an amino group,
(5) a hydroxy group,
(6) a C 1-6 alkyl group optionally having from 1 to 5 substituents selected from
(i) a halogen atom,
(ii) a cyano group,
(iii) a hydroxy group, and
(iv) a C 1-6 alkoxy group,

(7) a C 1-6 alkoxy group optionally having from 1 to 3 halogen atoms,
(8) a C 2-6 alkenyl group, and
(9) a C 3-6 cycloalkyl group; or

(II) a C 1-6 alkyl group substituted by from 1 to 3 substituents selected from the group consisting of
(1) a hydroxy group,
(2) a C 1-6 alkoxy-carbonyl group,
(3) a carboxy group,
(4) a piperidylcarbonyl group,
(5) a C 3-6 cycloalkyl group optionally substituted by from 1 to 3 C 1-6 alkyl groups,
(6) a phenyl group substituted by from 1 to 3 halogen atoms, and
(7) a tetrahydrofuryl group, a pyrrolidinyl group, a piperidyl group, a pyrazolyl group, a tetrahydropyranyl group, a pyridyl group, or a 7-oxabicyclo[2.2.1]heptyl group, each of which optionally has from 1 to 3 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy-carbonyl group;

X 1 , X 2 , and X 3 are selected from following combinations:
(1) X 1 is —CH═, X 2 is —CH═, and X 3 is —N═;
(2) X 1 is —N═, X 2 is —CH═, and X 3 is —N═, and
(3) X 1 is —CH═, X 2 is —CH═, and X 3 is —CH═;

or a salt thereof.

2. The compound according to claim 1 , wherein R 1 is a C 3-8 cycloalkyl group, a phenyl group, a pyridyl group, or a tetrahydropyranyl group, each of which is optionally substituted by from 1 to 3 substituents selected from the group consisting of
(1) a halogen atom,
(2) a cyano group,
(3) a hydroxy group,
(4) a C 1-6 alkyl group optionally having from 1 to 5 substituents selected from the group consisting of
(i) a halogen atom,
(ii) a cyano group,
(iii) a hydroxy group, and
(iv) a C 1-6 alkoxy group,

(5) a C 1-6 alkoxy group optionally having from 1 to 3 halogen atoms, and
(6) a C 3-6 cycloalkyl group; and

ring A is a benzene ring or a pyridine ring, each of which is substituted by from 1 to 3 substituents selected from
(1) a halogen atom,
(2) a carbamoyl group,
(3) a pyrazolyl group substituted by from 1 to 3 C 1-6 alkyl groups, and
(4) a triazolyl group substituted by from 1 or 2 C 1-6 alkyl groups;

or a salt thereof.

3. The compound according to claim 1 , wherein R 1 is a phenyl group or a pyridyl group, each of which is optionally substituted by from 1 to 3 substituents selected from the group consisting of
(1) a halogen atom,
(2) a cyano group,
(3) a C 1-6 alkyl group optionally having from 1 to 3 halogen atoms,
(4) a C 1-6 alkoxy group optionally having from 1 to 3 halogen atoms, and
(5) a C 3-6 cycloalkyl group; and

ring A is a benzene ring or a pyridine ring, each of which is substituted by from 1 to 3 substituents selected from the group consisting of
(1) a halogen atom,
(2) a carbamoyl group,
(3) a pyrazolyl group substituted by from 1 to 3 C 1-6 alkyl groups, and
(4) a triazolyl group substituted by from 1 or 2 C 1-6 alkyl groups;

or a salt thereof.

4. The compound according to claim 1 , wherein R 1 is (I) a C 3-8 cycloalkyl group, a phenyl group, a pyridyl group, or a tetrahydropyranyl group, each of which is substituted by from 1 to 3 substituents selected from the group consisting of
(1) a halogen atom,
(2) a cyano group,
(3) a hydroxy group, and
(4) a C 1-6 alkyl group substituted by from 1 to 3 halogen atoms; or

(II) a C 1-6 alkyl group substituted by from 1 to 3 substituents selected from the group consisting of
(1) a phenyl group substituted by from 1 to 3 halogen atoms, and
(2) a tetrahydrofuryl group; and

ring A is a benzene ring or a pyridine ring, each of which is substituted by from 1 to 3 substituents selected from the group consisting of
(1) a halogen atom,
(2) a carbamoyl group,
(3) a pyrazolyl group substituted by from 1 to 3 C 1-6 alkyl groups, and
(4) a triazolyl group substituted by 1 or 2 C 1-6 alkyl groups;

or a salt thereof.

5. The compound according to claim 1 , wherein R 1 is a phenyl group or a pyridyl group, each of which is substituted by from 1 to 3 substituents selected from the group consisting of
(1) a halogen atom,
(2) a cyano group, and
(3) a C 1-6 alkyl group substituted by from 1 to 3 halogen atoms;

ring A is a benzene ring or a pyridine ring, each of which is substituted by from 1 to 3 substituents selected from the group consisting of
(1) a halogen atom,
(2) a carbamoyl group,
(3) a pyrazolyl group substituted by from 1 to 3 C 1-6 alkyl groups, and
(4) a triazolyl group substituted by from 1 or 2 C 1-6 alkyl groups; and

X 1 , X 2 , and X 3 are selected from following combinations:
(1) X 1 is —CH═, X 2 is —CH═, and X 3 is —N═; and
(2) X 1 is —N═, X 2 is —CH═, and X 3 is —N═;
or a salt thereof.

6. 2-(4-(1-Methyl-1H-pyrazol-4-yl)benzyl)-7-((tetrahydrofuran-2-yl)methoxy)isoindolin-1-one, or a salt thereof.

7. 3-Fluoro-2-((2-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl)oxy)benzonitrile, or a salt thereof.

8. 4-((2,4-Difluorobenzyl)oxy)-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, or a salt thereof.

9. 4-((4-(2-Fluoro-4-(trifluoromethyl)phenoxy)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)benzamide, or a salt thereof.

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

11. The pharmaceutical composition according to claim 10 , which is a cholinergic muscarinic M1 receptor positive allosteric modulator.

12. 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.

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Sugimoto Takahiro
• Nakamura Minoru
• Sakamoto Hiroki
• Suzuki Shinkichi
• Yamada Masami
• Kamata Makoto
• Kojima Takuto
• Fujimori Ikuo
• Shimokawa Kenichiro

Classifications

• A61P43/00

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

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/20

  Hypnotics; Sedatives · 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

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title