Isoindoline-1-one derivatives as cholinergic muscarinic M1 receptor positive alloesteric modulator activity for the treatment of Alzheimers disease

1. A method for a treatment of Alzheimer's disease, schizophrenia, cognitive impairment associated with schizophrenia, pain, sleep disorder, Parkinson's disease dementia, Parkinson's disease, or dementia with Lewy bodies, in a mammal, which comprises administering to the mammal an effective amount of a compound represented by formula (I) below:

wherein

R 1 is an optionally substituted 5- or 6-membered cyclic group or an optionally substituted C 1-6 alkyl group;

R 2 and R 3 are the same or different, and each of R 2 and R 3 independently is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group, or an optionally substituted C 3-6 cycloalkyl group;

R 4 is a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted carbamoyl group, or an optionally substituted 3- to 8-membered cyclic group; and

Ring A is an optionally further substituted 6-membered aromatic ring,

or a salt thereof.

2. The method according to claim 1 , wherein R 1 is

(1) an optionally substituted phenyl group,

(2) an optionally substituted C 5-6 cycloalkyl group,

(3) an optionally substituted 5- or 6-membered non-aromatic heterocyclic group,

(4) an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, or

(5) an optionally substituted C 1-6 alkyl group.

3. The method according to claim 1 , wherein R 4 is

(1) a halogen atom,

(2) a cyano group,

(3) a C 1-6 alkyl group,

(4) an optionally substituted C 1-6 alkoxy group,

(5) an optionally substituted carbamoyl group, or

(6) an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group.

4. The method according to claim 1 , wherein Ring A is a 6-membered aromatic ring optionally further substituted by 1 to 3 substituents, in addition to R 4 ,

selected from

(a) a halogen atom,

(b) a C 1-6 alkyl group, and

(c) a C 1-6 alkoxy group.

5. The method according to claim 1 , wherein

R 1 is

(1) an optionally substituted phenyl group,

(2) an optionally substituted C 5-6 cycloalkyl group,

(3) an optionally substituted 5- or 6-membered non-aromatic heterocyclic group,

(4) an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, or

(5) an optionally substituted C 1-6 alkyl group;

R 2 is

(1) a hydrogen atom,

(2) a halogen atom, or

(3) an optionally substituted C 1-6 alkyl group;

R 3 is

(1) a hydrogen atom,

(2) a halogen atom,

(3) a cyano group,

(4) an optionally substituted C 1-6 alkyl group,

(5) a C 1-6 alkoxy group, or

(6) a C 3-6 cycloalkyl group;

R 4 is

(1) a halogen atom,

(2) a cyano group,

(3) a C 1-6 alkyl group,

(4) an optionally substituted C 1-6 alkoxy group,

(5) an optionally substituted carbamoyl group, or

(6) an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group; and

Ring A is a 6-membered aromatic ring optionally further substituted by 1 to 3 substituents, in addition to R 4 , selected from

(a) a halogen atom,

(b) a C 1-6 alkyl group, and

(c) a C 1-6 alkoxy group.

6. The method according to claim 1 , wherein

R 1 is

(1) a phenyl group optionally substituted by 1 to 3 substituents selected from

(i) a halogen atom, and

(ii) a cyano group,

(2) a C 5-6 cycloalkyl group optionally substituted by 1 to 3 substituents selected from

(i) a hydroxy group,

(ii) a C 1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, and

(iii) a C 1-6 alkoxy group,

(3) a 5- or 6-membered monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups,

(4) a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 halogen atoms, or

(5) a C 1-6 alkyl group optionally substituted by from 1 to 3 substituents selected from

(i) a hydroxy group, and

(ii) a 3- to 8-membered monocyclic non-aromatic heterocyclic group;

R 2 is

(1) a hydrogen atom,

(2) a halogen atom, or

(3) a C 1-6 alkyl group;

R 3 is

(1) a hydrogen atom,

(2) a halogen atom,

(3) a cyano group,

(4) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,

(5) a C 1-6 alkoxy group, or

(6) a C 3-6 cycloalkyl group;

R 4 is

(1) a halogen atom,

(2) a cyano group,

(3) a C 1-6 alkyl group,

(4) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms,

(5) a carbamoyl group,

(6) a mono- or di-C 1-6 alkyl-carbamoyl group, or

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

Ring A is a 6-membered aromatic ring optionally further substituted by 1 to 3 substituents, in addition to R 4 , selected from

(a) a halogen atom,

(b) a C 1-6 alkyl group, and

(c) a C 1-6 alkoxy group.

7. The method according to claim 6 , wherein the partial structure represented by the following formula:

in the formula (I) is a partial structure represented by the following formula:

8. The method according to claim 1 , wherein

R 1 is

(1) a phenyl group optionally substituted by 1 to 3 substituents selected from

(i) a halogen atom, and

(ii) a cyano group,

(2) a C 5-6 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups,

(3) a 5- or 6-membered monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups, or

(4) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from

(i) a hydroxy group, and

(ii) a 3- to 8-membered monocyclic non-aromatic heterocyclic group;

R 2 is

(1) a hydrogen atom,

(2) a halogen atom, or

(3) a C 1-6 alkyl group;

R 3 is

(1) a hydrogen atom,

(2) a halogen atom,

(3) a cyano group,

(4) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,

(5) a C 1-6 alkoxy group, or

(6) a C 3-6 cycloalkyl group;

R 4 is

(1) a halogen atom,

(2) a cyano group,

(3) a C 1-6 alkyl group,

(4) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms,

(5) a mono- or di-C 1-6 alkyl-carbamoyl group, or

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

Ring A is a 6-membered aromatic ring optionally further substituted by 1 to 3 substituents, in addition to R 4 , selected from

(a) a halogen atom, and

(b) a C 1-6 alkoxy group.

9. The method according to claim 8 , wherein the partial structure represented by the following formula:

in the formula (I) is a partial structure represented by the following formula:

10. The method according to claim 1 , wherein

R 1 is

(1) a C 5-6 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups, or

(2) a 5- or 6-membered monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups;

R 2 is

(1) a halogen atom, or

(2) a C 1-6 alkyl group;

R 3 is a C 1-6 alkyl group;

R 4 is

(1) a C 1-6 alkyl group,

(2) a C 1-6 alkoxy group, or

(3) a 5- or 6-membered monocyclic aromatic heterocyclic group; and

Ring A is a benzene ring or a pyridine ring, each of which is unsubstituted, in addition to R 4 .

11. The method according to claim 10 , wherein the partial structure represented by the following formula:

in the formula (I) is a partial structure represented by the following formula:

12. The method according to claim 1 , wherein

R 1 is

(1) a cyclohexyl group substituted by one hydroxy group, or

(2) a tetrahydropyranyl group substituted by one hydroxy group;

R 2 is

(1) a halogen atom, or

(2) a C 1-6 alkyl group;

R 3 is a C 1-6 alkyl group;

R 4 is

(1) a C 1-6 alkyl group,

(2) a C 1-6 alkoxy group, or

(3) a pyrazolyl group; and

Ring A is a benzene ring or a pyridine ring, each of which is unsubstituted, in addition to R 4 .

13. The method according to claim 12 , wherein the partial structure represented by the following formula:

in the formula (I) is a partial structure represented by the following formula: