Triazolyl pyrimidinone compounds as PDE2 inhibitors

Patent metadata

Field	Value
Publication number	US-10358435-B2
Application number	US-201615554614-A
Country	US
Kind code	B2
Filing date	Mar 11, 2016
Priority date	Mar 17, 2015
Publication date	Jul 23, 2019
Grant date	Jul 23, 2019

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 or solvate thereof, wherein:
J represents pyrimidinone optionally substituted with 1 to 2 groups selected from C 1-6 alkyl, C 2-6 alkenyl, (CH 2 ) n C 3-10 cycloalkyl, and (CH 2 ) n C 6-10 aryl, said alkyl and aryl optionally substituted with one to three groups of R a ;
Y is triazolyl optionally substituted with R b ;
R 2 is selected from the group consisting of CR x R y ;
or R 2 and the available carbon atom and/or nitrogen atom of the Y triazolyl can combine to form an 8 to 10 membered heterocyclyl optionally interrupted with one or more heteroatoms selected from O, S, and N, and said heterocyclyl optionally substituted with 1 to 3 groups of R b ;
R x and R y are independently selected from the group consisting of H, (CH 2 ) n OR, C 1-6 alkyl, C 3-6 cycloalkyl, C(O)OR and N(R) 2 , said alkyl optionally substituted with one to three groups of R a ;
R represents H, or C 1-6 alkyl,
R x and R y can combine with the carbon atom to which they are attached to form a group selected from C═O, C 3-6 cycloalkyl and C 3-6 heterocyclyl;
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 H, 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 wherein the pyrimidinone is represented by structural formula I^

wherein R 1 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, (CH 2 ) n C 3-10 cycloalkyl, and (CH 2 ) n C 6-10 aryl, said alkyl and aryl optionally substituted with one to three groups of R a .

3. The compound according to claim 2 wherein R 1 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, pentyl, ethenyl, butenyl, and propenyl.

4. The compound according to claim 2 wherein R 1 is (CH 2 ) n C 3-10 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

5. The compound according to claim 2 wherein R 1 is (CH 2 ) n C 6-10 aryl wherein the aryl is optionally substituted phenyl.

6. The compound according to claim 1 wherein R 2 is selected from the group consisting of CH(CH 2 ) n CH 3 , C(CH 3 ) 2 , CH(CH(CH 3 ) 2 ), CH 2 , —C(═O)—, CH (CH 2 ) n OH, C(CH 3 )(OH), CHC(O)OCH 3 , CH(NHCH 3 ), CH(CH 2 )n(OCH 3 ), CH-cyclopropyl, and cyclobutyl.

7. The compound according to claim 6 wherein R 2 is CH(CH 2 ) n CH 3 .

8. The compound according to claim 1 wherein R 2 and an available carbon atom and/or nitrogen atoms of the Y triazolyl combine to form a C 8-10 heterocyclyl selected from the group consisting of tetrahydrotriazolopyridinyl, dihydrotriazolooxazinyl, dihydropyrrolotriazolyl and tetrahydrotriazoloazepinyl.

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

or a pharmaceutically acceptable salt or solvate thereof.

10. The compound according to claim 9 wherein Y—R 2 is selected from the group consisting of

R b is hydrogen, R 1 is selected from the group consisting of optionally substituted C 1-6 alkyl cyclopropyl, cyclobutyl, and (CH 2 ) n phenyl and R 2 is selected from the group consisting of CH(CH 2 ) n CH 3 , CHCH(CH 3 ) 2 , CH 2 , CH(CH 2 ) n OH.

11. The compound according to claim 10 wherein Y is (a), R b is H or CH 3 , and R 1 is optionally substituted methyl, and R 2 is CH(CH 2 ) n CH 3 .

12. The compound according to claim 10 wherein Y is (b), R b is H or CH 3 , and R 1 is optionally substituted methyl, and R 2 is CH(CH 2 ) n CH 3 .

13. The compound according to claim 10 wherein Y is (d), R b is H or CH 3 , and R 1 is optionally substituted methyl, and R 2 is CH(CH 2 ) n CH 3 .

14. The compound according to claim 10 wherein Y is (f), R b is H or CH 3 , and R 1 is optionally substituted methyl, and R 2 is CH(CH 2 ) n CH 3 .

15. The compound according to claim 10 wherein the Y triazole is (a), (b), (c), (d), or (e) R 1 is optionally substituted methyl, and R 2 and R b combine to form an optionally substituted ring fused to the triazole.

16. The compound according to claim 15 wherein the fused triazole ring is selected from the group consisting of optionally substituted tetrahydrotriazolopyridinyl, dihydrotriazolooxazinyl, dihydropyrrolotriazolyl, and tetrahydrotriazoloazepinyl.

17. A compound which is:
(R)-6-(2-(1-(2-Chloro-4-(trifluoromethyl)phenyl)ethyl)-2H-1,2,3-triazol-4-yl)-2-methylpyrimidin-4(3H)-one,
(S)-6-(2-(1-(2-Chloro-4-(trifluoromethyl)phenyl)ethyl)-2H-1,2,3-triazol-4-yl)-2-methylpyrimidin-4(3H)-one,
(S)-6-(1-(1-(2-Chloro-4-(trifluoromethyl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidin-4(3H)-one,
(R)-6-(1-(1-(2-Chloro-4-(trifluoromethyl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidin-4(3H)-one,
(R)-6-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2H-1,2,3-triazol-4-yl)-2-methylpyrimidin-4(3H)-one,
(S)-6-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2H-1,2,3-triazol-4-yl)-2-methylpyrimidin-4(3H)-one,
(R)-2-methyl-6-(2-(1-(2-methyl-4-(trifluoromethyl)phenyl)ethyl)-2H-1,2,3-triazol-4-yl)pyrimidin-4(3H)-one,
(S)-2-methyl-6-(2-(1-(2-methyl-4-(trifluoromethyl)phenyl)ethyl)-2H-1,2,3-triazol-4-yl)pyrimidin-4(3H)-one,
(R)-6-(2-(1-(2-chloro-4-ethylphenyl)ethyl)-2H-1,2,3-triazol-4-yl)-2-methylpyrimidin-4(3H)-one,
(S)-6-(2-(1-(2-chloro-4-ethylphenyl)ethyl)-2H-1,2,3-triazol-4-yl)-2-methylpyrimidin-4(3H)-one,
(R)-2-methyl-6-(1-(1-(2-methyl-4-(trifluoromethyl)phenyl)-ethyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4(3H)-one,
(S)-2-methyl-6-(1-(1-(2-methyl-4-(trifluoromethyl)phenyl)-ethyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4(3H)-one,
2-methyl-6-(1-(1-(4-(trifluoromethoxy)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4(3H)-one,
2-benzyl-6-(1-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4(3H)-one,
6-(1-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidin-4(3H)-one,
2-(cyclopropylmethyl)-6-(1-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4(3H)-one,
(E)-2-(but-1-enyl)-6-(1-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4(3H)-one,
2-methyl-6-(1-(1-(4-(pentafluorosulfanyl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4(3H)-one,
(R)-2-methyl-6-(1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4(3H)-one,
(S)-2-methyl-6-(1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4(3H)-one,
(R)-6-(1-(1-(2-chloro-4-ethylphenyl)ethyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidin-4(3H)-one,
(S)-6-(1-(1-(2-chloro-4-ethylphenyl)ethyl)-1H-1,2,3-triazol-4-yl)-2-me

Assignees

• Merck Sharp & Dohme
• Shen Dong Ming
• Sinz Christopher J
• Crespo Alejandro
• Wilson Johnathan E
• Mccracken Troy
• Xu Shimin
• Li Haitang

Inventors

• Shen Dong-Ming
• Sinz Christopher J
• Crespo Alejandro
• Wilson Johnathan E
• Mccracken Troy
• Xu Shimin
• Li Haitang

Classifications

• C07D498/04

  Ortho-condensed systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4192

  1,2,3-Triazoles · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title