IP Library › Granted Patent US 12,247,031
Granted Patent B2
US 12,247,031 · App. 17/299,634 · Granted Mar 11, 2025

Cyclobutyl pyrazolopyrimidine PDE9 inhibitors

Inventors: Ashok Arasappan (Bridgewater, NJ); Jason M. Cox (Flemington, NJ); John S. Debenham (Scotch Plains, NJ); Zhuyan Guo (Scotch Plains, NJ); Zhong Lai (East Brunswick, NJ); Dongfang Meng (Morganville, NJ)
Assignee: Merck Sharp & Dohme LLC
C07D487/04A61K31/519A61P13/12A61P25/18C07D519/00
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Quick Facts
Patent No.
US 12,247,031
App. No.
17/299,634
Granted
Mar 11, 2025
Kind
B2
Abstract

The present invention is directed to cyclobutyl pyrazolopyrimidine compounds which may be useful as therapeutic agents for the treatment of disorders associated with phosphodiesterase 9 (PDE9). The present invention also relates to the use of such compounds for treating cardiovascular and cerebrovascular diseases, such as hypertension, chronic kidney disease and heart failure, and neurological and psychiatric disorders, such as schizophrenia, psychosis or Huntington's disease, and those associated with striatal hypofunction or basal ganglia dysfunction.

Claims (105)

1. A compound which is selected from:

6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-(2-(pyridin-2-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-((1R,2R)-2-(pyridin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-((1S,2S)-2-(pyridin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-((1R,2R)-2-(pyridin-2-yl)cyclobutyl)-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-((1S,2S)-2-(pyridin-2-yl)cyclobutyl)-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

2-(2-(3-cyano-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl)cyclobutyl)pyridine 1-oxide;

2-((1R,2R)-2-(3-cyano-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidin-6-yl)cyclobutyl)pyridine 1-oxide;

2-((1S,2S)-2-(3-cyano-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidin-6-yl)cyclobutyl)pyridine 1-oxide;

2-((1R,2R)-2-(3-cyano-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidin-6-yl)cyclobutyl)pyridine 1-oxide;

2-((1S,2S)-2-(3-cyano-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidin-6-yl)cyclobutyl)pyridine 1-oxide;

6-(2-(5,6-dihydro-4H-pyrrolo [1,2-b] pyrazol-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(5,6-dihydro-4H-pyrrolo [1,2-b] pyrazol-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(5,6-dihydro-4H-pyrrolo [1,2-b] pyrazol-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(5,6-dihydro-4H-pyrrolo [1,2-b] pyrazol-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(5,6-dihydro-4H-pyrrolo [1,2-b] pyrazol-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-(2-(5-fluoropyridin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(5-fluoropyridin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(5-fluoropyridin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(5-fluoropyridin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(5-fluoropyridin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-(2-(3-fluoropyridin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(3-fluoropyridin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(3-fluoropyridin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(3-fluoropyridin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(3-fluoropyridin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-(2-(1-methyl-1H-pyrazol-3-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(1-methyl-1H-pyrazol-3-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(1-methyl-1H-pyrazol-3-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(1-methyl-1H-pyrazol-3-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(1-methyl-1H-pyrazol-3-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-(2-(1-methyl-1H-pyrazol-5-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-(2-(4-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(4-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(4-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(4-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(4-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-(2-(3-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(3-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(3-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(3-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(3-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-(2-(3-oxomorpholino) cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-((1R,2R)-2-(3-oxomorpholino) cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-((1S,2S)-2-(3-oxomorpholino) cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-((1R,2R)-2-(3-oxomorpholino) cyclobutyl)-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-((1S,2S)-2-(3-oxomorpholino) cyclobutyl)-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-((1R,2R)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-((1S,2S)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-((1R,2R)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

4-oxo-6-((1S,2S)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-(2-(4-fluoro-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(4-fluoro-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(4-fluoro-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(4-fluoro-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(4-fluoro-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-(2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-(2-(4-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(4-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(4-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(4-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(4-cyclopropyl-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-(2-(4-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-(2-(4-(difluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(4-(difluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(4-(difluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(4-(difluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(4-(difluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-(2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-(2-(4-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(4-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1S,2S)-2-(4-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

6-((1R,2R)-2-(4-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile; and

6-((1S,2S)-2-(4-cyano-1H-pyrazol-1-yl)cyclobutyl)-4-oxo-1-((R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo [3,4-d]pyrimidine-3-carbonitrile;

or a pharmaceutically acceptable salt thereof.

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

3. A method for treating a disorder or disease associated with PDE9 dysfunction in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. A method for treating cardiovascular disease, cerebrovascular disease, hypertension, chronic kidney disease or heart failure in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. A method for treating psychotic disorders, delusional disorders, drug induced psychosis, anxiety disorders, movement disorders, mood disorders or neurodegenerative disorders in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

Assignments (2)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 3, 2021
From: ARASAPPAN, ASHOK; COX, JASON M.; DEBENHAM, JOHN S.; GUO, ZHUYAN; LAI, ZHONG; MENG, DONGFANG
To: MERCK SHARP & DOHME CORP.
Reel/Frame 056431/0979 →