Substituted triazolo bicyclic compounds as PDE2 inhibitors

Patent metadata

Field	Value
Publication number	US-10357481-B2
Application number	US-201615579878-A
Country	US
Kind code	B2
Filing date	Jun 27, 2016
Priority date	Jul 1, 2015
Publication date	Jul 23, 2019
Grant date	Jul 23, 2019

Abstract

The present invention is directed to substituted triazolo bicyclic 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 Ia

or a pharmaceutically acceptable salt thereof, wherein:
one of R 1 and R 2 is H and the other is C 1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups R a ;
or R 1 and R 2 can combine with the carbon to which they are attached to form C 3-10 cycloalkyl or C 3-10 -heterocycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and oxetanyl, said cycloalkyl and heterocycloalkyl optionally substituted with 1 to 3 groups R a ;
R 4a is selected from the group consisting of H, CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 20 H, C(CH 3 ) 3 , CH 2 CH 3 , CH(CH 3 )OH, (CH 2 ) n OH, CHF 2 , CH 2 F, CF 3 , CF 2 CF 3 , NH 2 , N(CH 3 ) 2 , NHCH 3 , OCH 2 CH 3 , (CH 2 ) n OCH 3 , halo and optionally substituted cyclopropyl;
Rob is hydrogen or CH3;
R a is selected from the group consisting of halo, CN, C 1-6 alkyl, (CH 2 ) n OR, (O) p C 1-4 haloalkyl, NR 2 , SCF 3 , and SF 5 , said alkyl optionally substituted with one to three groups selected from halo, wherein halo is selected from the group consisting of fluorine and chlorine, and C 1-6 alkyl; or
two adjacent R a groups on the phenyl together with the atoms to which they are attached can combine to form a cyclic ring, said ring optionally interrupted by 1 to 2 heteroatoms selected from N, S, and O;
R represents H or C 1-6 alkyl,
n represents 0, 1, 2, 3, or 4;
p represents 0 or 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein one of R 1 and R 2 is H 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 ) n OH, C(CH 3 ) 2 NH 2 , C(CH 2 CH 3 ) 2 OH, N(CH 3 ) 2 , NHCH 3 , OCH 2 CH 3 , and (CH 2 ) n OCH 3 .

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R a is selected from halo, (CH 2 ) n CF 3 , OCF 3 , C(CH 3 ) 3 , CHF 2 , SF 5 , SCF 3 , OCHF 2 , CH(CH 3 ) 2 , or when two adjacent R a on the phenyl along with the atoms to which they are attached combine the combination of two R a is selected from cyclopropyl or pyridyl, said cyclopropyl and pyridyl optionally substituted with 1 to 3 groups of C 1-6 alkyl,
X, Y and Z, respectively, represents X=N, Y=CR 4a , Z=CR 4b , wherein R 4a and R 4b are selected from the group consisting of H, CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 2 OH, C(CH 3 ) 3 , CH 2 CH 3 , CH(CH 3 )OH, (CH 2 ) n OH, CHF 2 , CH 2 F, CF 3 , CF 2 CF 3 , NH 2 , N(CH 3 ) 2 , NHCH 3 , OCH 2 CH 3 , (CH 2 ) n OCH 3 , halo and optionally substituted cyclopropyl, and
one of R 1 and R 2 is H and the other is selected from the group consisting H, 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 ) n OH, C(CH 3 ) 2 NH 2 , C(CH 2 CH 3 ) 2 OH, N(CH 3 ) 2 , NHCH 3 , OCH 2 CH 3 , and (CH 2 ) n OCH 3 .

4. The compound according to 36 or a pharmaceutically acceptable salt thereof wherein R a is selected from the group consisting of halo, (CH2)nCF3, and OCF3, one of R 4a and R 4b is hydrogen or CH 3 and the other is selected from the group consisting of H, CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 2 OH, C(CH 3 ) 3 , CH 2 CH 3 , CH(CH 3 )OH, (CH 2 ) n OH, CHF 2 , CH 2 F, CF 3 , CF2CF 3 , NH 2 , N(CH 3 ) 2 , NHCH 3 , OCH 2 CH 3 , (CH 2 ) n OCH 3 , halo and optionally substituted cyclopropyl, and one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 2 OH, C(CH 3 ) 3 , (CH 2 ) n OH, and (CH 2 ) n OCH 3 .

5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof wherein R a is selected from the group consisting of fluorine, chlorine, CF 3 , and OCF 3 , one of R 4a and R 4b is hydrogen and the other is selected from the group consisting of CH 3 , (CH 2 ) n OH, and CF 3 , and one of R 1 and R 2 is hydrogen and the other is CH 3 .

6. The compound according to claim 3 or a pharmaceutically acceptable salt thereof wherein R a is selected from the group consisting of fluorine, chlorine, CF 3 , and OCF 3 , one of R 4a and R 4b is hydrogen and the other is selected from the group consisting of CH 3 , (CH 2 ) n OH, and CF 3 , and R 1 and R 2 combine with the carbon to which they are attached to form optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or oxetanyl.

7. A compound which is:
5-Methyl-N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
5-Methyl-N-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-{(1R)-1-[3-Fluoro-4-(trifluoromethyl)phenyl]ethyl}-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
5-Methyl-N-{(1R)-1-[4-(2,2,2-trifluoroethyl)phenyl]ethyl}[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-{(1R)-1-[3-Chloro-4-(trifluoromethyl)phenyl]ethyl}-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-{(1R)-1-[2,5-Difluoro-4-(trifluoromethyl)phenyl]ethyl}-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
5-Methyl-N-{(1R)-1-[4-(trifluoromethoxy)phenyl]ethyl}[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-{(1R)-1-[3-Fluoro-4-(trifluoromethoxy)phenyl]ethyl}-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-{(1R)-1-[3-Chloro-4-(trifluoromethoxy)phenyl]ethyl}-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
5-Methyl-N-[(1R)-1-{4-[(trifluoromethyl)sulfanyl]phenyl}ethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-[(1R)-1-{3-Fluoro-4-[(trifluoromethyl)sulfanyl]phenyl}ethyl]-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
5-Methyl-N-{(1R)-1-[4-(pentafluoro-λ 6 -sulfanyl)phenyl]ethyl}[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
5-Methyl-N-{(1R)-1-[4-(1-methylethyl)phenyl]ethyl}[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-[(1R)-1-(4-Cyclopropyl-3-fluorophenyl)ethyl]-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
5-Methyl-N-{(1R)-1-[4-(1-methylcyclopropyl)phenyl]ethyl}[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-{(1R)-1-[3-Fluoro-4-(trifluoromethyl)phenyl]propyl}-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
5-Methyl-N-[(1R)-1-{4-[(trifluoromethyl)sulfanyl]phenyl}propyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-[(1R)-1-{3-Fluoro-4-[(trifluoromethyl)sulfanyl]phenyl}propyl]-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
5-Methyl-N-{(1R)-2-methyl-1-[4-(trifluoromethyl)phenyl]propyl}[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-{(1R)-1-[3-Fluoro-4-(trifluoromethyl)phenyl}-2-methylpropyl]-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-[(1R)-1-{3-Fluoro-4-[(trifluoromethyl)sulfanyl]phenyl}-2-methylpropyl]-5-methyl[1,2,4]triazolo [1,5-a]pyrimidin-7-amine,
5-Methyl-N-{(1R)-2-methyl-1-[4-(pentafluoro-λ 6 -sulfanyl)phenyl]propyl}[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-{(1R)-1-[4-(Difluoromethoxy)phenyl]-2-methylpropyl}-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
5-Methyl-N-{(1R)-2-methyl-1-[4-(1-methylcyclopropyl)phenyl]propyl}[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-[(1R)-1-(4-Cyclopropyl-3-fluorophenyl)-2-methylpropyl]-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-{(1R)-2,2-Dimethyl-1-[4-(trifluoromethyl)phenyl]propyl}-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-{(1R)-1-[3-Fluoro-4-(trifluoromethyl)phenyl]-2,2-dimethylpropyl}-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-{(1R)-1-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2,2-dimethylpropyl}-5-methyl[1,2,4]triazolo [1,5-a]pyrimidin-7-amine,
N-[(1R)-2,2-Dimethyl-1-{4-[(trifluoromethyl)sulfanyl]phenyl}propyl]-5-methyl[1,2,4]triazolo [1,5-a]pyrimidin-7-amine,
N-[(1R)-1-(4-Cyclopropylphenyl)-2,2-dimethylpropyl]-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,
N-[(1R)

Assignees

• Merck Sharp & Dohme
• Morriello Gregori J
• Chang Lehua
• Forster Ashley
• Chen Yili
• Dwyer Michael P
• Guo Zack Zhiqiang
• Wang Ming
• Xu Shimin
• Bo Yingjian
• Fu Jianmin

Inventors

• Morriello Gregori J
• Chang Lehua
• Forster Ashley
• Chen Yili
• Dwyer Michael P
• Guo Zack Zhiqiang
• Wang Ming
• Xu Shimin
• Bo Yingjian
• Fu Jianmin

Classifications

• A61K31/52

  Purines, e.g. adenine · CPC title

• A61K31/4196 Primary

  1,2,4-Triazoles · 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

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/18

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