Heteroaryl-pyrimidinone compounds as PDE2 inhibitors

Patent metadata

Field	Value
Publication number	US-10195201-B2
Application number	US-201615571192-A
Country	US
Kind code	B2
Filing date	May 2, 2016
Priority date	May 5, 2015
Publication date	Feb 5, 2019
Grant date	Feb 5, 2019

Abstract

The present invention is directed to substituted pyrimidinone 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 of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, and (CH 2 ) n C 6-10 aryl, said alkyl, cycloalkyl, and aryl optionally substituted with one to three groups of R a ;
R 2 and R 2a are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, (CH 2 )nOR, C(O)OR, N(R) 2 , C 3-10 cycloalkyl, (CH 2 ) n C 5-10 heterocyclyl said alkyl, cycloalkyl, and heterocyclyl optionally substituted with one to three groups of R b ;
R 2 and R 2a can combine with the carbon atom to which they are attached to form a C 2-6 alkenyl, C 3-6 cycloalkyl, or C 4-10 heterocyclyl, said alkenyl, cycloalkyl and heterocyclyl optionally substituted with one to three groups of R b ;
Y is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, and imidazolyl, said group optionally substituted with one to three groups of R b ;
R represents H, or C 1-6 alkyl,
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, C(O)OR, —O(CH 2 ) n N(R) 2 , (CHR) n N(R) 2 , NO 2 , SCF 3 , S(O) s CF 3 , S(O) s R, SF 5 , C 3-10 cycloalkyl, O—C 3-10 cycloalkyl, C 5-10 heterocyclyl, and C 6-10 aryl, said alkyl, cycloalkyl, heterocyclyl and aryl optionally substituted with one to three groups of R b ;
R b is selected from the group consisting of halo, C 1-6 alkyl, (CH 2 ) n OR, and (O) p C 1-4 haloalkyl;
n represents 0, 1, 2, 3, or 4;
s represents 0, 1, or 2; and
p represents 0 or 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl represented by structural formulas (a), (b), (c), (d), (e), (f), (g), (h), (i) and (j):

3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted pyridyl represented by structural formula (a), (b), (c) or (j).

4. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted pyrimidinyl represented by structural formula (d), (e), or (f).

5. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted pyrazinyl represented by structural formula (g).

6. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted pyridazinyl represented by structural formula (h) or (i).

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein Y is optionally substituted oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl represented by structural formulas (k), (1), (m), (n), (o), (p), (q), (r), (s), (t), (u), (v), and (w):

8. The compound according to claim 7 , or a pharmaceutically acceptable salt thereof wherein Y is optionally substituted thiazolyl represented by structural formula (k), (1), (m), or (n).

9. The compound according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein Y is thiadiazolyl represented by structural formula (o).

10. The compound according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted oxazolyl represented by structural formula (p) or (q).

11. The compound according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein Y is oxadiazolyl represented by structural formula (r), (s) or (t).

12. The compound according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted imidazolyl represented by structural formula (u), (v) or (w).

13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof wherein R is hydrogen, R 1 is C 1-6 alkyl optionally substituted with 1 to 3 groups of R a , R 2 and R 2a are independently selected from hydrogen, (CH 2 ) n CH 3 , CH 3 , CH(CH3) 2 , (CH 2 ) n OH, C(O)OCH 3 , NHCH 3 , (CH 2 ) n (OCH 3 ), cyclopropyl, cyclobutyl, tetrahydrofuranyl, 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 , OC(CH 3 ) 2 , CH 2 F, CHF 2 , CF 3 , OCHF 2 , OCF 3 , SCH 3 , SCF 3 , SF 5 , SOCF 3 , SO 2 CF 3 , SO 2 CH 3 , CH 2 NH 2 , (CH 2 ) n N(CH 3 ) 2 , NO 2 , CN, cyclobutyl, cyclopropyl, and phenyl, said groups, optionally substituted with one to three groups of Rb.

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof wherein one of R 2 and R 2a is hydrogen and the other is selected from the group consisting of (CH 2 ) n CH 3 , CH 3 , CH(CH3) 2 , (CH 2 ) n OH, C(O)OCH 3 , NHCH 3 , (CH 2 ) n (OCH 3 ), cyclopropyl, cyclobutyl, and tetrahydrofuranyl.

15. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof wherein the number of R b present is zero, R 1 is optionally substituted methyl optionally substituted with 1 to 3 groups of R a , and one of R 2 and R 2a is hydrogen and the other is (CH 2 ) n CH 3 .

16. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof wherein Y is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl, said groups optionally substituted with 1 to 3 groups of R a , R is hydrogen, R 1 is methyl optionally substituted with 1 to 3 groups of R a , and one of R 2 and R 2a is hydrogen and the other is selected from (CH 2 ) n CH 3 , CH 3 , CH(CH 3 ) 2 , (CH 2 ) n OH, C(O)OCH 3 , NHCH 3 , (CH 2 ) n (OCH 3 ), cyclopropyl, cyclobutyl, and tetrahydrofuranyl.

17. A compound which is:
2-Methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)thiazol-2-yl)pyrimidin-4(3H)-one,
2-Methyl-6-(2-(1-(4-(trifluoromethyl)phenyl)ethyl)thiazol-4-yl)pyrimidin-4(3H)-one,
2-Methyl-6-(4-(1-(4-(trifluoromethyl)phenyl)ethyl)thiazol-2-yl)pyrimidin-4(3H)-one,
(S)-6-(5-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1,3,4-thiadiazol-2-yl)-2-methylpyrimidin-4(3H)-one,
(R)-6-(5-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1,3,4-thiadiazol-2-yl)-2-methylpyrimidin-4(3H)-one,
(S)-2-methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)-1,3,4-thiadiazol-2-yl)pyrimidin-4(3H)-one,
(R)-2-methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)-1,3,4-thiadiazol-2-yl)pyrimidin-4(3H)-one,
2-Methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)oxazol-2-yl)pyrimidin-4(3H)-one,
(S)-2-methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-4(3H)-one,
(R)-2-methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-4(3H)-one,
2-Methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-4(3H)-one,
2-Methyl-6-(3-(1-(4-(trifluoromethyl)phenyl)ethyl)-1,2,4-oxadiazol-5-yl)pyrimidin-4(3H)one,
2-Methyl-6-(5-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazol-2-yl)pyrimidin-4(3H)-one,
(S)-6-(1-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1H-imidazol-4-yl)-2-methylpyrimidin-4(3H)-one,
(R)-6-(1-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1H-imid

Assignees

• Merck Sharp & Dohme

Inventors

• Shen Dong-Ming
• Wilson Jonathan E
• Mccracken Troy

Classifications

• A61P25/22

  Anxiolytics · CPC title

• C07D239/36

  as doubly bound oxygen atom or as unsubstituted hydroxy radical · CPC title

• A61K31/513 Primary

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title