Substituted pyrazolo[3,4-d]pyrimidines as PDE9 inhibitors

Patent metadata

Field	Value
Publication number	US-10934294-B2
Application number	US-201816001295-A
Country	US
Kind code	B2
Filing date	Jun 6, 2018
Priority date	Jun 8, 2017
Publication date	Mar 2, 2021
Grant date	Mar 2, 2021

Abstract

The present invention is directed to pyrazolopyrimidine compounds of the general structural formula I:

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.

First claim

What is claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
A is cyclobutyl, which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro and methyl;
R 1 , R 2 and R 3 are independently hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl, —O—C 1-6 alkyl, C 2-6 alkynyl, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and fluoro, and further wherein the —O—C 1-6 alkyl is optionally substituted with one or more fluoro substituents;
R 4 is hydrogen, methyl, trifluoromethyl, hydroxymethyl, ethyl or carboxy;
R 5 is cyclohexyl, tetrahydropyranyl, phenyl, pyrazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, wherein the cyclohexyl, tetrahydropyranyl, phenyl, pyrazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl is substituted with one or more substituents independently selected from the group consisting of R 1a , R 1b and R 1c ; and
R 1a , R 1b and R 1c are independently hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl, —O—C 1-6 alkyl, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and fluoro, and further wherein the —O—C 1-6 alkyl is optionally substituted with one or more fluoro substituents;
with the proviso that the compound is other than:
1-((S)-1-(4-fluorophenyl)ethyl)-4-oxo-6((1S,2S)-2-(pyrmidin-2-yl) cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
4-oxo-6-((1S,2S-2-(pyrimidin-2-yl)cyclobutyl)-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-(difluoromethoxy)pyrimidin-2-yl)cyclobuty)-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-(fluoropyrimidin-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;
1-((S)-1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl) cyclobuty)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile; or
6-((1S,2S)-2-(4-cyclopropylpyrimidin-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.

2. The compound of claim 1 , wherein the compound is of formula Ia:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is cyclobutyl, which is optionally substituted with one or more fluoro substituents.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and R 3 are independently hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl, —O—C 1-6 alkyl, C 2-4 alkynyl, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and fluoro, and further wherein the —O—C 1-6 alkyl is optionally substituted with one or more fluoro substituents.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen;
R 2 is hydrogen, fluoro, chloro, bromo, hydroxy, methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, ethynyl or cyclopropyl; and
R 3 is hydrogen.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein;
R 1a is hydrogen, fluoro, cyano, methyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy;
R 1b is hydrogen; and
R 1c is hydrogen.

8. A pharmaceutical composition comprising an inert carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

9. A method for inhibiting phosphodiesterase 9 activity in a mammalian patient, comprising administering to the mammalian patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 , wherein the mammalian patient has a disorder or disease associated with phosphodiesterase 9 dysfunction.

11. The method of claim 10 , wherein the disorder or disease associated with phosphodiesterase 9 dysfunction is selected from the group consisting of drug induced psychosis, a psychotic disorder, a delusional disorder, a movement disorder, a neurodegenerative disorder and an anxiety disorder.

12. The method of claim 10 , wherein the disorder or disease associated with phosphodiesterase 9 dysfunction is selected from the group consisting of hypertension, heart failure, a cardiovascular disease, a cerebrovascular disease, and a chronic kidney disease.

13. A compound selected from the group consisting of:
1-(1-(4-fluorophenyl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
1-((S)-1-(4-fluorophenyl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
1-((S)-1-(4-fluorophenyl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
1-((R)-1-(4-fluorophenyl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
1-((R)-1-(4-fluorophenyl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
4-oxo-6-(2-(pyrimidin-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-(pyrimidin-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-(pyrimidin-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-(pyrimidin-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-((1 S, 2 S)-2-(pyrimidin-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-(2-(pyrimidin-2-yl)cyclobutyl)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
1-[1-(4-cyanophenyl)ethyl]-4-oxo-6-(2-pyrimidin-2-ylcyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
1-((S)-1-(4-cyanophenyl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
1-((S)-1-(4-cyanophenyl)ethyl)-4-oxo-6-((1 S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
1-((R)-1-(4-cyanophenyl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
1-((R)-1-(4-cyanophenyl)ethyl)-4-oxo-6-((1 S,

Assignees

• Merck Sharp & Dohme

Inventors

• Arasappan Ashok
• Cox Jason M
• Debenham John S
• Guo Zhuyan
• He Jiafang
• Hussain Zahid
• Lai Zhong
• Li Derun
• Meng Dongfang
• Raghavan Subharekha
• Tyagarajan Sriram

Classifications

• A61P25/18

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title