Heteroaromatic compounds and their use as dopamine D1 ligands

• US 9,107,923 B2
• Filed: 03/04/2015
• Issued: 08/18/2015
• Est. Priority Date: 06/27/2013
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Brodney, Michael Aaron, Davoren, Jennifer Elizabeth, Dounay, Amy Beth, Gray, David Lawrence Firman, Green, Michael Eric, Henderson, Jaclyn Louise, Mente, Scot Richard, O'Neil, Steven Victor, Rogers, Bruce Nelsen, Zhang, Lei, Efremov, Ivan Viktorovich, Lee, Chewah
• Primary Examiner(s): Balasubramanian, Venkataraman
• Application Number:
  US14/638,677
• Publication Number:
  US 20150196561A1
• Time in Patent Office: 167 Days
• Field of Search: 544/310, 514/269, 514/274
• US Class Current: 1/1
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• 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: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/12 for electrolyte homeostasis
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/12 : Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings

Abstract

The present invention provides, in part, compounds of Formula I:

and pharmaceutically acceptable salts thereof; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating D1-mediated (or D1-associated) disorders including, e.g., schizophrenia (e.g., its cognitive and negative symptoms), cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD, PD, or pharmacotherapy therapy), age-related cognitive decline, dementia, and Parkinson'"'"'s disease.

Claims

1. A compound selected from the group consisting of:

6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione;

1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine-2,4(1H,3H)-dione; and

6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein the compound is selected from the group consisting of:

(−

)-6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione;

(+)-6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione;

(−

)-1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine-2,4(1H,3H)-dione;

(+)-1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine-2,4(1H,3H)-dione;

(−

)-6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; and

(+)-6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione,

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 that is 6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 that is 6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione.

5. The pharmaceutically acceptable salt of the compound of claim 3.

9. The compound of claim 1 that is 1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 that is 1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine-2,4(1H,3H)-dione.

11. The pharmaceutically acceptable salt of claim 9.

15. The compound of claim 1 that is 6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15 that is 6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione.

17. The pharmaceutically acceptable salt of the compound of claim 15.

21. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of the compound of claim 3 and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of the compound of claim 9 and a pharmaceutically acceptable carrier.

28. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of the compound of claim 15 and a pharmaceutically acceptable carrier.

6. A compound that is (−

)-6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 that is (−

)-6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione.

8. The pharmaceutically acceptable salt of the compound of claim of 6.

23. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of the compound of claim 6 and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable carrier.

12. A compound that is (+1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12 that is (+1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine-2,4(1H,3H)-dione.

14. The pharmaceutically acceptable salt of the compound of claim of 12.

26. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of the compound of claim 12 and a pharmaceutically acceptable carrier.

27. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable carrier.

18. A compound that is (−

)-6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18 that is (−

)-6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione.

20. The pharmaceutically acceptable salt of the compound of claim of 18.

29. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of the compound of claim 18 and a pharmaceutically acceptable carrier.

30. A pharmaceutical composition comprising the compound of claim 19 and a pharmaceutically acceptable carrier.