Bicyclic heterocyclic compounds as PDE2 inhibitors

Patent metadata

Field	Value
Publication number	US-10287293-B2
Application number	US-201615736202-A
Country	US
Kind code	B2
Filing date	Jun 27, 2016
Priority date	Jul 1, 2015
Publication date	May 14, 2019
Grant date	May 14, 2019

Abstract

The present invention is directed to dihydropyrazolopyrimidinone compounds of formulas (I) and (II) 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 of structural formulas I and II:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 represents hydrogen, or C 1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of R b ,
R 2 represents OR, NR 2 , C 1-6 alkyl, (CH 2 ) 1-4 OR, C 1-4 haloalkyl, C(O)C 6-10 aryl, —(CH 2 ) n C 6-10 aryl, (CH 2 ) n C 3-10 heterocyclyl or (CH 2 ) n C 3-10 cycloalkyl wherein when R 2 is a heterocyclyl it is attached to the pyrazolopyrimidinone or imidazotriazinone ring through a carbon atom, and wherein said alkyl, aryl, heterocyclyl and cycloalkyl are optionally substituted with 1 to 3 groups of R a
R 3 and R 3a independently represent hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl, said alkyl, and cycloalkyl, optionally substituted with 1 to 3 groups of R a ,
or R 3 and R 3a can combine with the carbon atom to which they are attached to form a C 3-6 cycloalkyl, or C 4-10 heterocycloalkyl, said alkyl, cycloalkyl, and heterocycloalkyl optionally substituted with 1 to 3 groups of R a ,
R represents hydrogen, or C 1-6 alkyl,
R a is selected from the group consisting of hydrogen, halo, CN, SCF 3 , SF 5 , C 1-6 alkyl, (CH 2 ) n OR, (CH 2 ) n C 1-4 haloalkyl, O—C 1-4 haloalkyl, C 3-6 cycloalkyl, said alkyl and cycloalkyl optionally substituted with 1 to 3 groups of C 1-6 alkyl or halo;
R b is selected from the group consisting of halo, CN, C 1-6 alkyl, (CH 2 ) n OR, (CH 2 ) n C 1-4 haloalkyl, O—C 1-4 haloalkyl, and
n represents 0, 1, 2, 3, or 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is C 1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of R b .

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof wherein the optionally substituted C 1-6 alkyl of R 1 is selected from the group consisting of CH 3 , CH 2 OH, CH 2 CH 2 OH, CH 2 CN, CH 2 CF 3 , CH 2 CH 2 F, CH 2 CH 2 CF 3 , CH 2 CHF 2 , CH(CH 2 OH)CH 3 .

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 is optionally substituted C 1-6 alkyl.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof wherein R 2 is selected from the group consisting OR, and NR 2 , (CH 2 ) n CH 3 , CH(CH 3 ) 2 , and C(CH 3 ) 3 .

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 and R 3a independently represent hydrogen or optionally substituted C 1-6 alkyl.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof wherein R 3 and R 3a independently represent methyl, ethyl, propyl, isopropyl, butyl, CH 2 OH, CH 2 CH 2 OH, CH 2 CN, CH 2 CF 3 , CH 2 CH 2 F, CH 2 CH 2 CF 3 , CH 2 CHF 2 , or CH(CH 2 OH)CH 3 .

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R a is selected from OH, halo, (CH 2 ) n CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , (CH 2 ) n OCH 3 , OCH(CH 3 ) 2 , CH 2 F, CHF 2 , (CH 2 ) n CF 3 , CF 2 CH 3 , OCHF 2 , OCF 3 , CF 2 CF 3 , cyclobutyl, cyclopropyl said groups optionally substituted with 1 to 3 groups of C 1-6 alkyl or halo.

9. The compound according to claim 1 represented by structural formula Ia:

or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted C 1-6 alkyl selected from the group consisting of CH 3 , CH 2 CH 2 OH, CH 2 CN, CH 2 CF 3 , CH 2 CH 2 F, CH 2 CH 2 CF 3 , CH(CH 2 OH)CH 3 , and R a is selected from OH, halo, (CH 2 ) n CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , (CH 2 ) n OCH 3 , OCH(CH 3 ) 2 , CH 2 F, CHF 2 , (CH 2 ) n CF 3 , CF 2 CH 3 , OCHF 2 , OCF 3 , CF 2 CF 3 , cyclobutyl, cyclopropyl said groups optionally substituted with 1 to 3 groups of C 1-6 alkyl or halo.

11. The compound according to claim 9 or a pharmaceutically acceptable salt thereof wherein R 2 is selected from the group consisting OR, NR 2 , (CH 2 ) n CH 3 , CH(CH 3 ) 2 , and C(CH 3 ) 3 .

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, CH 2 OH, CH 2 CH 2 OH, CH 2 CN, CH 2 CF 3 , CH 2 CH 2 F, CH 2 CH 2 CF 3 , CH 2 CHF 2 , and CH(CH 2 OH)CH 3 .

13. The compound according to 9 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted C 1-6 alkyl selected from the group consisting of CH 3 , CH 2 CH 2 OH, CH 2 CN, CH 2 CF 3 , CH 2 CH 2 F, CH 2 CH 2 CF 3 , CH(CH 2 OH)CH 3 , R 2 and R 3 are methyl, and R a is selected from OH, halo, (CH 2 ) n CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , (CH 2 ) n OCH 3 , OCH(CH 3 ) 2 , CH 2 F, CHF 2 , (CH 2 ) n CF 3 , CF 2 CH 3 , OCHF 2 , OCF 3 , CF 2 CF 3 , cyclobutyl, cyclopropyl said groups optionally substituted with 1 to 3 groups of C 1-6 alkyl or halo.

14. The compound of claim 1 of formula II represented by structural formula IIa:

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted C 1-6 alkyl selected from the group consisting of CH 3 , CH 2 OH, CH 2 CH 2 OH, CH 2 CN, CH 2 CF 3 , CH 2 CH 2 F, CH 2 CH 2 CF 3 , CH(CH 2 OH)CH 3 , and R a is selected from OH, halo, (CH 2 ) n CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , (CH 2 ) n OCH 3 , OCH(CH 3 ) 2 , CH 2 F, CHF 2 , (CH 2 ) n CF 3 , CF 2 CH 3 , OCHF 2 , OCF 3 , CF 2 CF 3 , cyclobutyl, cyclopropyl said groups optionally substituted with 1 to 3 groups of C 1-6 alkyl or halo.

16. The compound according to claim 14 or a pharmaceutically acceptable salt thereof wherein R 2 is selected from the group consisting OR, NR 2 , (CH 2 ) n CH 3 , CH(CH 3 ) 2 , and C(CH 3 ) 3 .

17. The compound according to claim 14 or a pharmaceutically acceptable salt thereof wherein R 3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, CH 2 OH, CH 2 CH 2 OH, CH 2 CN, CH 2 CF 3 , CH 2 CH 2 F, CH 2 CH 2 CF 3 , CH 2 CHF 2 , and CH(CH 2 OH)CH 3 .

18. The compound according to claim 14 or a pharmaceutically acceptable salt thereof wherein R 1 is optionally substituted C 1-6 alkyl selected from the group consisting of CH 3 , CH 2 OH, CH 2 CH 2 OH, CH 2 CN, CH 2 CF 3 , CH 2 CH 2 F, CH 2 CH 2 CF 3 , CH(CH 2 OH)CH 3 , R 2 and R 3 are methyl, and R a is selected from OH, halo, (CH 2 ) n CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , (CH 2 ) n OCH 3 , OCH(CH 3 ) 2 , CH 2 F, CHF 2 , (CH 2 ) n CF 3 , CF 2 CH 3 , OCHF 2 , OCF 3 , CF 2 CF 3 , cyclobutyl, cyclopropyl said groups optionally substituted with 1 to 3 groups of C 1-6 alkyl or halo.

19. The compound according to claim 1 wherein R 3 and R 3a combine with the carbon atom to which they are attached to form a C 3-6 cycloalkyl, or C 4-10 heterocycloalkyl, said alkyl, cycloalkyl, and heterocycloalkyl optionally substituted with 1 to 3 groups of R a .

20. A compound which is selected from the group consisting of:
(R)-5-Methyl-3-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,
(5)-5-Methyl-3-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,
(R)-1-

Assignees

• Merck Sharp & Dohme
• Stachel Shawn J
• Sinz Christopher J
• Chen Yili
• Wilson Jonathan E
• Dwyer Michael P
• Paone Daniel V
• Xu Shimin

Inventors

• Stachel Shawn J
• Dwyer Michael P
• Sinz Christopher J
• Wilson Jonathan E
• Paone Daniel V
• Chen Yili
• Xu Shimin

Classifications

• A61P25/18

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P25/06

  Antimigraine agents · 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