US 2022/0017526 A1Published application

Pyrazolopyrimidine pde9 inhibitors

AssigneeMerck Sharp & Dohme Corp.

InventorsAshok Arasappan, Jason M. Cox, John S. Debenham, Zhe Feng, Zhuyan Guo, Dongfang Meng

Life of this patent

Estimating the term…

Abstract

The present invention is directed to amino and alkyl 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.

Claims14

Dependent claims

A compound of the formula I:

wherein:
X is —N(R6)— or —C(R8R9)—;
Y is —N═ or —CH═;
Z is —N═ or —CH═;
R1, R2 and R3 are independently selected from:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C1-6alkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy and fluoro,
(5) —O—C1-6alkyl, which is unsubstituted or substituted with substituents selected from fluoro,
(6) C3-6cycloalkyl,
(7) C2-6alkynyl, and
(8) —CN;
R4 is selected from:
(1) hydrogen,
(2) —CH3;
(3) —CF3,
(4) —CH2OH,
(5) —CO2H, and
(6) —CH2CH3;
R5 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 R1a, R1b and R1c, wherein R1a, R1b and R1c are independently selected from:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C1-6alkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy and fluoro,
(5) —O—C1-6alkyl, which is unsubstituted or substituted with substituents selected from fluoro,
(6) C3-6cycloalkyl,
(7) azetidine, morpholine, piperidine, or pyrrolidine, and
(8) —CN;
R6 is selected from:
(1) hydrogen, and
(2) C1-6alkyl;
R7 is selected from:
(1) hydrogen,
(2) C1-6alkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy and fluoro,
(3) C2-6alkenyl,
(4) C3-6cycloalkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy and fluoro, and
(5) azetidine, morpholine, piperidine, or pyrrolidine;
or R6 and R7 and the —CH—N— to which they are attached are joined to form an azetidine or a pyrrolidine ring;
R8 and R9 are independently selected from:
(1) hydrogen, and
(2) C1-6alkyl;
or a pharmaceutically acceptable salt thereof.

44 more elements

A compound which is selected from:

1-(1-(6-cyclopropylpyridin-3-yl)ethyl)-6-(methyl(1-(pyrimidin-2-yl)propyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-[methyl(1-pyrimidin-2-ylethyl)amino]-4-oxo-1-[1-[6-(trifluoromethyl)-3-pyridyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-[methyl(1-pyrimidin-2-ylpropyl)amino]-4-oxo-1-[1-[6-(trifluoromethyl)-3-pyridyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-[methyl(1-pyrimidin-2-ylpropyl)amino]-4-oxo-1-[1-[4-(trifluoromethyl)phenyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-[1-[5-(difluoromethyl)pyrimidin-2-yl]propyl-methyl-amino]-4-oxo-1-[1-[6-(trifluoromethyl)-3-pyridyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-[methyl-(2-methyl-1-pyrimidin-2-yl-propyl)amino]-4-oxo-1-[1-[6-(trifluoromethyl)-3-pyridyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-[[cyclopropyl(pyrimidin-2-yl)methyl]-methyl-amino]-4-oxo-1-[1-[6-(trifluoromethyl)-3-pyridyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-[[cyclobutyl(pyrimidin-2-yl)methyl]-methyl-amino]-4-oxo-1-[1-[6-(trifluoromethyl)-3-pyridyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-[1-(5-fluoro-2-pyridyl)propyl-methyl-amino]-4-oxo-1-[1-[6-(trifluoromethyl)-3-pyridyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-[1-(5-fluoropyrimidin-2-yl)propyl-methyl-amino]-4-oxo-1-(1-tetrahydropyran-4-ylethyl)-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-[methyl(1-pyrimidin-2-ylpent-4-enyl)amino]-4-oxo-1-[1-[6-(trifluoromethyl)-3-pyridyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
4-oxo-6-(2-pyrimidin-2-ylazetidin-1-yl)-1-[1-[6-(trifluoromethyl)-3-pyridyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-[2-(4-fluorophenyl)azetidin-1-yl]-4-oxo-1-[1-[6-(trifluoromethyl)-3-pyridyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
4-oxo-6-(2-pyrimidin-2-ylpyrrolidin-1-yl)-1-[1-[6-(trifluoromethyl)-3-pyridyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-[2-(4-fluorophenyl)azetidin-1-yl]-4-oxo-1-[1-[6-(trifluoromethyl)-3-pyridyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-[methyl-[1-[5-(trifluoromethoxy)pyrimidin-2-yl]propyl]amino]-4-oxo-1-[1-[6-(trifluoromethyl)-3-pyridyl]ethyl]-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
1-[1-(6-cyclopropyl-3-pyridyl)ethyl]-6-[1-(5-fluoropyrimidin-2-yl)propyl-methyl-amino]-4-oxo-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
1-[1-(4-cyclopropylphenyl)ethyl]-6-[1-(5-fluoropyrimidin-2-yl)propyl-methyl-amino]-4-oxo-5H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
4-oxo-6-((1-(pyrimidin-2-yl)propyl)amino)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-((1-(5-fluoropyrimidin-2-yl)propyl)(methyl)amino)-4-oxo-1-(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)ethyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
6-(2-(5-cyclopropylpyrimidin-2-yl)ethyl)-4-oxo-1-(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)propyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
and
4-oxo-6-(2-(pyrimidin-2-yl)butyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
or a pharmaceutically acceptable salt thereof.

23 more elements

Dependencies are inferred from the claim text.

patentgrep

Loading patent…

Abstract