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US 10,647,727 B2Granted
Substituted pyrazolo/imidazolo bicyclic compounds as PDE2 inhibitors
AssigneeMerck Sharp & Dohme Corp.
InventorsGregori J. Morriello, Lehua Chang, Ashley Forster, Richard Berger, Kausik K. Nanda, William D. Shipe
Life of this patent
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Abstract
The present invention is directed to pyrimidine carboxamide compounds of formula I which are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 2 (PDE2). The present invention also relates to the use of such compounds for treating neurological and psychiatric disorders, such as schizophrenia, psychosis, Parkinson's disease, Parkinson's disease dementia (PDD), or Huntington's disease, and those associated with striatal hypofunction or basal ganglia dysfunction.
Claims12
A compound represented by structural formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- X represents NH, or O;
- R is selected from the group consisting of H and C1-6alkyl,
- one of R1 and R2 is hydrogen and the other is C1-6alkyl, said alkyl is optionally substituted with 1 to 3 groups of Ra;
- or R1 and R2 can combine with the carbon to which they are attached to form a C3-10cycloalkyl or C3-10heterocycloalkyl, said cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 3 groups of Ra, wherein when R1 and R2 are combined Ra is selected from the group consisting of (CH2)nCF3, OCF3, C(CH3)3, OC(CH3)3, CHF2, SF5, SCF3, OCHF2, and CH(CH3)2;
- R3 represents halo, C1-6alkyl, C1-4haloalkyl, (CH2)nOR, C3-10cycloalkyl, or CN, said alkyl and cycloalkyl are optionally substituted with 1 to 3 groups of Ra;
- R4 is selected from the group consisting of hydrogen, (CH2)nOR, C1-6alkyl, (CH2)nC1-4haloalkyl, CN, and N(R)2, said alkyl is optionally substituted with one to three groups of Ra;
- Ra is selected from the group consisting of halo, CN, C1-6alkyl, (CH2)nOR, (CH2)nCF3, (O)pC1-4haloalkyl, N(R)2, SCF3, SF5, C3-10cycloalkyl, C6-10aryl, and C4-10heterocyclyl;
- n represents 0, 1, 2, 3, or 4;
- and
- provided that when X is NH, then R1 and R2 combine with the carbon to which they are attached to form a C3-10cycloalkyl or C3-10heterocycloalkyl, said cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 3 groups of Ra;
- and
- p represents 0 or 1.
10 more elements
A compound which is:
- 6-Chloro-1-methyl-N-{1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-1-methyl-N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-1-methyl-N-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-1-methyl-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-1-methyl-N-{1-[4-(1-methylethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-1-methyl-N-{1-(4-[1-methylethyl)phenyl]propyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-1-methyl-N-{1-[4-(1H-pyrazol-1-yl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-1-methyl-N-{1-methyl-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-1-methyl-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1H-pyrazolo[3,4-d]pyrimidin-amine,
- 6-Chloro-N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-N-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 1-Methyl-4-({1-[4-(trifluoromethyl)phenyl]cyclopropyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-6-ol,
- 6-Cyclopropyl-1-methyl-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-N,1-dimethyl-N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-N,1-dimethyl-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-N-ethyl-1-methyl-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-N,1-dimethyl-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 6-Chloro-1-(1-methylethyl)-N-{1-[4-(trifluoromethyl)phenyl]ethyl}1-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 1-Methyl-6-(trifluoromethyl)-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 1,6-Dimethyl-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 1,6-Dimethyl-N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- N-{1-[3-Fluoro-4-(trifluoromethoxy)phenyl]cyclopropyl}-1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 1,6-Dimethyl-N-(1-{4-[(trifluoromethyl)sulfanyl]phenyl}cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- N-{1-[2-Fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}-1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 1,6-Dimethyl-N-{1-[4-(trifluoromethyl)phenyl]cyclobutyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- N,1,6-Trimethyl-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- N,1,6-Trimethyl-N-(1-{4-[(trifluoromethyl)sulfanyl]phenyl}cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- N-{1-[3-Fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}-6-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
- 1-Methyl-4-({1-[4-(trifluoromethyl)phenyl]cyclopropyl}amino)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile, or
- 1,6-Dimethyl-4-({1-[4-(trifluoromethyl)phenyl]cyclopropyl}oxy)-1H-pyrazolo[3,4-d]pyrimidine,
- or a pharmaceutically acceptable salt thereof.
28 more elements
Dependencies are inferred from the claim text.