Substituted pyrazolo/imidazolo bicyclic compounds as PDE2 inhibitors

Patent metadata

Field	Value
Publication number	US-10647727-B2
Application number	US-201615579115-A
Country	US
Kind code	B2
Filing date	Jun 20, 2016
Priority date	Jun 25, 2015
Publication date	May 12, 2020
Grant date	May 12, 2020

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.

First claim

What is claimed is:

1. 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 C 1-6 alkyl,
one of R 1 and R 2 is hydrogen and the other is C 1-6 alkyl, said alkyl is optionally substituted with 1 to 3 groups of R a ;
or R 1 and R 2 can combine with the carbon to which they are attached to form a C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, said cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 3 groups of R a , wherein when R 1 and R 2 are combined R a is selected from the group consisting of (CH 2 ) n CF 3 , OCF 3 , C(CH 3 ) 3 , OC(CH 3 ) 3 , CHF 2 , SF 5 , SCF 3 , OCHF 2 , and CH(CH 3 ) 2 ;
R 3 represents halo, C 1-6 alkyl, C 1-4 haloalkyl, (CH 2 ) n OR, C 3-10 cycloalkyl, or CN, said alkyl and cycloalkyl are optionally substituted with 1 to 3 groups of R a ;
R 4 is selected from the group consisting of hydrogen, (CH 2 ) n OR, C 1-6 alkyl, (CH 2 ) n C 1-4 haloalkyl, CN, and N(R) 2 , said alkyl is optionally substituted with one to three groups of R a ;
R a is selected from the group consisting of halo, CN, C 1-6 alkyl, (CH 2 ) n OR, (CH 2 ) n CF 3 , (O) p C 1-4 haloalkyl, N(R) 2 , SCF 3 , SF 5 , C 3-10 cycloalkyl, C 6-10 aryl, and C 4-10 heterocyclyl;
n represents 0, 1, 2, 3, or 4; and
provided that when X is NH, then R 1 and R 2 combine with the carbon to which they are attached to form a C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, said cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 3 groups of R a ; and

p represents 0 or 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein X is NH.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 4 is hydrogen.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 4 is selected from the group consisting of H, CH 3 , (CH 2 ) n OH, C(CH 3 ) 2 OH, C(CH 3 ) 3 , CH(CH 3 ) 2 , CH 2 C(CH 3 ) 2 OH, CH 2 CH 3 (CH 2 ) n CHF 2 , (CH 2 ) n CH 2 F, (CH 2 ) n CF 3 , NH 2 , N(CH 3 ) 2 , NHCH 3 , OCH 2 CH 3 , (CH 2 ) n OCH 3 , and CN.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof wherein R 4 is selected from the group consisting of CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 2 OH, C(CH 3 ) 3 , CH 2 CH 3 , (CH 2 ) n OH, CHF 2 , CH 2 F, CH 2 CF 3 , CF 3 , and NH 2 .

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein X is O, and one of R 1 and R 2 is hydrogen and the other is selected from the group consisting CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 2 OH, C(CH 3 ) 2 CH 2 OH, C(CH 3 ) 3 , CH 2 CH 3 , CH(CH 3 )OH, (CH 2 ) 1-4 OH, C(CH 3 ) 2 NH 2 , C(CH 2 CH 3 ) 2 OH, and (CH 2 ) 1-4 OCH 3 .

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein X is NH, and R 1 and R 2 combine with the carbon to which they are attached to form an optionally substituted C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or oxetanyl, said C 3-10 cycloalkyl or C 3-10 heterocycloalkyl are optionally substituted with 1 to 3 groups selected from R a where R a is selected from the group consisting of (CH 2 ) n CF 3 , OCF 3 , C(CH 3 ) 3 , OC(CH 3 ) 3 , CHF 2 , SF 5 , SCF 3 , OCHF 2 , and CH(CH 3 ) 2 .

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is selected from the group consisting of halo, OH, (CH 2 ) n CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , (CH 2 ) n OCH 3 , CH 2 F, CHF 2 , (CH 2 ) n CF 3 , CN, and cyclopropyl optionally substituted with 1 to 3 groups of R a .

9. 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.

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

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein
when X is O, R a is selected from the group consisting of (CH 2 ) n CF 3 , OCF 3 , C(CH 3 ) 3 , OC(CH 3 ) 3 , CHF 2 , SF 5 , SCF 3 , OCHF 2 , and CH(CH 3 ) 2 ; R 3 is selected from the group consisting of halo, OH, (CH 2 ) n CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , (CH 2 ) n OCH 3 , CH 2 F, CHF 2 , (CH 2 ) 1-3 CF 3 , CN, and cyclopropyl optionally substituted with 1 to 3 groups of R a ; R 4 is selected from the group consisting of (CH 2 ) n OH, CH(CH 3 ) 2 , CH 3 , and CH 2 CF 3 ; and one of R 1 and R 2 is hydrogen and the other

Assignees

• Merck Sharp & Dohme
• Morriello Gregori J
• Dwyer Michael P
• Chang Lehua
• Chen Yili
• Wang Ming
• Forster Ashley
• Berger Richard
• Nanda Kausik K
• Bunda Jamie L
• Shipe William D

Inventors

• Morriello Gregori J
• Chang Lehua
• Forster Ashley
• Berger Richard
• Nanda Kausik K
• Shipe William D

Classifications

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• A61P25/18

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

• A61P25/16

  Anti-Parkinson drugs · CPC title

• C07D473/34

  attached in position 6, e.g. adenine · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title