6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one allosteric modulators of the M4 muscarinic acetylcholine receptor

Patent metadata

Field	Value
Publication number	US-10351564-B2
Application number	US-201816176608-A
Country	US
Kind code	B2
Filing date	Oct 31, 2018
Priority date	Dec 23, 2015
Publication date	Jul 16, 2019
Grant date	Jul 16, 2019

Abstract

The present invention is directed to 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one compounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which M4 muscarinic acetylcholine receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which M4 muscarinic acetylcholine receptors are involved.

First claim

What is claimed is:

1. A compound which is selected from:
2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3-((1-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)benzonitrile;
3-methyl-2-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3-methyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3-methyl-2-(4-((5-methylpyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin 5-one;
2-(4-(isochroman-7-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3-methyl-2-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
2-[4-(1,3-dihydro-2-benzofuran-5-yloxy)piperidin-1-yl]-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3-methyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
2-(4-((2,3-dihydrobenzofuran-6-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
2-(4-(isochroman-6-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
3,4-dimethyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
6-(2-hydroxyethyl)-3,4-dimethyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
6-(2-hydroxyethyl)-3,4-dimethyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; and
2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 which is:
2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 which is:
3-((1-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)benzonitrile;
or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 which is:
3-methyl-2-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 which is:
3-methyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 which is:
3-methyl-2-(4-((5-methylpyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 which is:
2-(4-(isochroman-7-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 which is:
3-methyl-2-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 which is:
2-[4-(1,3-dihydro-2-benzofuran-5-yloxy)piperidin-1-yl]-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 which is:
3-methyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 which is:
2-(4-((2,3-dihydrobenzofuran-6-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 which is:
2-(4-(isochroman-6-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 which is:
2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 which is:
3,4-dimethyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 which is:
6-(2-hydroxyethyl)-3,4-dimethyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 which is:
6-(2-hydroxyethyl)-3,4-dimethyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 which is:
2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;
or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

19. A method for the treatment of a neurological and/or psychiatric disorder characterized by muscarinic acetylcholine receptor dysfunction comprising the step of administering at least one compound of claim 1 , or a pharmaceutically acceptable salt of said compound, to a mammalian patient in need thereof in an amount effective for the treatment of said disorder.

20. The method of claim 19 , wherein the patient has been diagnosed with a need for treatment of the disorder prior to the administering step.

21. The method of claim 19 , wherein the disorder is a neurological and/or psychiatric disorder characterized by mAChR M4 dysfunction.

22. The method of claim 19 , wherein the disorder is a psychotic disorder.

23. The method of claim 22 , wherein the psychotic disorder is selected from schizophrenia, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic break, tardive psychosis, myxedematous psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, bipolar I disorder with psychotic features, and substance-induced psychotic disorder.

24. The method of claim 19 , wherein the disorder is a cognitive disorder.

25. The method of claim 24 , wherein the cognitive disorder is selected from amnesia, dementia, delirium, amnestic disorder, substance-induced persisting delirium, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, Parkinsonian-ALS demential complex, dementia of the Alzheimer's type, age-related cognitive decline, and mild cognitive impairment.

26. A method for the treatment of a disorder selected from schizophrenia, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, positive and negative symptoms of schizophrenia, secondary psychotic disorder, bipolar I disorder with psychotic features, and substance-induced psychotic disorder, in a human patient comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt of said compound, to the patient in need thereof in an amount effective for the treatment of said disorder.

27. A method for the treatment of a disorder selected from amnesia, dementia, del

Assignees

• Merck Sharp & Dohme
• Merck Sharop & Dohme Corp

Inventors

• Gao Xiaolei
• Knowles Sandra L
• Lo Michael Man-Chu
• Mazzola Jr Robert D

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07F9/222

  Amides of phosphoric acids · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title