Pyrazolopyrimidine pde9 inhibitors

Patent metadata

Field	Value
Publication number	US-2018354955-A1
Application number	US-201816001295-A
Country	US
Kind code	A1
Filing date	Jun 6, 2018
Priority date	Jun 8, 2017
Publication date	Dec 13, 2018
Grant date	—

Abstract

The present invention is directed to 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.

First claim

What is claimed is:

1 . A compound of the formula I:

wherein:
A is a cyclobutyl ring, which is unsubsubstituted or or substituted with substituents selected from: fluoro and methyl;
R 1 , R 2 and R 3 are independently selected from:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from: hydroxy and fluoro,
(5) —O—C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from fluoro,
(6) C 3-6 cycloalkyl,
(7) C 2-6 alkynyl, and
(8) —CN;

R 4 is selected from:
(1) hydrogen,
(2) —CH 3 ;

(3) —CF 3 ,
(4) —CH 2 OH,
(5) —CO 2 H, and
(6) —CH 2 CH 3 ;

R 5 is a phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiazolyl, cyclohexyl or tetrahydropyranyl ring, wherein the phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiazolyl, cyclohexyl or tetrahydropyranyl ring is substituted with R 1a , R 1b and R 1c , wherein R 1a , R 1b and R 1c are independently selected from:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from: hydroxy and fluoro,
(5) —O—C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from fluoro,
(6) C 3-6 cycloalkyl, and
(7) —CN;

or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 of the formula Ia:

or a pharmaceutically acceptable salt thereof.

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

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and R 3 are independently selected from:
(1) hydrogen, (2) halogen, (3) hydroxyl, (4) C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from: hydroxy and fluoro, (5) —O—C 1-6 alkyl, which is unsubstituted or substituted with substituents selected from fluoro, (6) C 3-6 cycloalkyl, (7) C 2-4 alkynyl, and (8) —CN.

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —CH 3 .

6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, R 3 is hydrogen and R 2 is selected from:
(1) hydrogen, (2) fluoro, (3) chloro, (4) bromo, (5) hydroxyl, (6) —CH 3 , (7) —OCH 3 , (8) —CHF 2 , (9) —CF 3 , (10) —OCHF 2 , (11) —OCF 3 , (12) —CH2CH 3 , (13) —CH(CH 3 ) 2 , (14) —C(CH3) 3 , (15) —C═CH, and (16) cyclopropyl.

7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1b is hydrogen and R 1c is hydrogen, and R 1a is selected from:
(1) hydrogen, (2) fluoro, (3) —CH 3 , (4) —CHF 2 , (5) —CF 3 , (6) —OCHF 2 , (7) —OCF 3 , and (8) —CN.

8 . A compound which is selected from:
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,25)-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-((1S,2S)-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-((1S,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-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile; 1-(1-(3,4-difluorophenyl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile; 1-((S)-1-(3,4-difluorophenyl)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-(3,4-difluorophenyl)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-(3,4-difluorophenyl)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-(3,4-difluorophenyl)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-ylcyclobutyl]-1-{1-[4-(trifluoromethyl)phenyl]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-(4-(trifluoromethyl)phenyl)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-(4-(trifluoromethyl)phenyl)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-(4-(trifluoromethyl)phenyl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile; 4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(4-(trifluoromethyl)phenyl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile; 4-oxo-6-[2-pyrimidin-2-ylcyclobutyl]-1-{1-[3-(trifluoromethyl)phenyl]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-(3-(trifluoromethyl)phenyl)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-(3-(trifluoromethyl)phenyl)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-(3-(trifluoromethyl)phenyl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile; 4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-

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

• A61P13/12

  of the kidneys · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P25/18

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