Pyrimidone carboxamide compounds as PDE2 inhibitors

Patent metadata

Field	Value
Publication number	US-9815796-B2
Application number	US-201415107233-A
Country	US
Kind code	B2
Filing date	Dec 17, 2014
Priority date	Dec 23, 2013
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

Disclosed are 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), pharmaceutical compositions and uses thereof.

First claim

The invention claimed is:

1. A compound represented by structural formula I

or a pharmaceutically acceptable salt or hydrate thereof, wherein:
A is CR 4 R 5 , C 3-6 cycloalkyl, or C 4-6 heterocyclyl, said cycloalkyl and heterocyclyl unsubstituted or substituted with 1 to 3 groups of R a ;
B is selected from the group consisting of phenyl, naphthyl, C 3-6 cycloalkyl, said phenyl, naphthyl, C 3-6 cycloalkyl, unsubstituted or substituted with 1 to 3 groups of R a ;
R is hydrogen or C 1-6 alkyl;
or R can combine with A and the nitrogen atom to which A is attached to form a five to six membered heterocycle, said heterocycle optionally substituted with one to three groups of R a ;
or R and B can combine with A and the nitrogen atom to which A is attached to form a five to ten membered heterocycle, said heterocycle optionally substituted with one to three groups of R a ;
R 1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkylSR, C 3-10 cycloalkyl, (CRR) n C 4-10 heterocyclyl, and (CRR) n C 6-10 aryl, said alkyl, cycloalkyl, heterocyclyl and aryl optionally substituted with one to three groups of R a ;
R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloallkyl, and C 1-4 haloalkyl;
R 4 and R 5 are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-4 hydroxyalkyl, and C 1-4 haloalkyl, (CH 2 ) n SC 1-6 alkyl, C(O)OR, C(O)N(R) 2 , CN, (CH 2 ) n C 5-10 heterocyclyl, and (CH 2 ) n C 6-10 aryl, said alkyl, cycloalkyl, heterocyclyl and aryl optionally substituted with one to three groups of R a ,
R a is selected from the group consisting of H, 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, 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,
with the proviso that the compound of formula I is not:
N-(1-(4-methoxyphenyl)propyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide,
N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide,
N-((4-Methoxyphenyl)(phenyl)methyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide,
N-(2,2-dimethylchroman-4-yl)-6-oxo-2-phenyl-1,6-dihydropyrimidine-4-carboxamide,
N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-phenylethyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide or
6-Oxo-N-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-1,6-dihydropyrimidine-4-carboxamide.

2. The compound according to claim 1 wherein A is CR 4 R 5 .

3. The compound according to claim 1 wherein A is C 3-6 cycloalkyl.

4. The compound according to claim 2 wherein one of R 4 and R 5 is hydrogen or CH 3 and the other is selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 1-4 haloalkyl, (CH 2 ) n SC 1-6 alkyl, C(O)OR, C(O)N(R) 2 , CN, (CH 2 ) n C 5-10 heterocyclyl, and (CH 2 ) n C 6-10 aryl, said alkyl, cycloalkyl, heterocyclyl and aryl optionally substituted with one to three groups of R a .

5. The compound according to claim 4 wherein one of R 4 and R 5 is hydrogen or CH 3 and the other is CH 3 , CH 2 CH 3 , C(CH 3 ) 2 , CH 2 OH, CH(CH 3 )OH, or C(CH 3 ) 2 OH, CN, C(O)OR C(O)N(R) 2 , cyclopropyl, cyclobutyl, cyclopentyl, tetrazolyl, or phenyl, said tetrazolyl and phenyl optionally substituted with one to three groups of R a .

6. The compound according to claim 5 wherein one of R 4 and R 5 is hydrogen and the other is CH 3 , CH 2 CH 3 , C(CH 3 ) 2 , CH 2 OH, CH(CH 3 )OH, C(CH 3 ) 2 OH, cyclopropyl, cyclobutyl, or cyclopentyl.

7. The compound according to claim 3 wherein the cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl.

8. The compound according to claim 1 wherein B is unsubstituted or substituted phenyl.

9. The compound according to claim 1 wherein B is unsubstituted or substituted naphthyl.

10. The compound according to claim 1 wherein R 1 is optionally substituted C 1-6 alkyl.

11. The compound according to claim 1 wherein R 1 is optionally substituted C 3-10 cycloalkyl.

12. The compound according to claim 1 wherein R 1 is optionally substituted (CRR) n C 5-10 heterocyclyl.

13. The compound according to claim 1 wherein R 1 is optionally substituted (CRR) n C 6-10 aryl.

14. The compound according to claim 1 of formula I represented by structural formula II:

and pharmaceutically acceptable salts and hydrates thereof.

15. The compound according to claim 1 wherein R 1 is selected from the group consisting of CH 3 , or CH 2 OCH 3 , cyclopropyl, cyclobutyl, or optionally substituted phenyl, pyrimidinyl, or pyrazolyl, one of R 4 and R 5 is hydrogen or CH 3 and the other is CH 3 , CH 2 CH 3 , C(CH 3 ) 2 , CH 2 OH, CH(CH 3 )OH, or C(CH 3 ) 2 OH, CN, C(O)OR C(O)N(R) 2 , cyclopropyl, cyclobutyl, cyclopentyl, tetrazolyl, or phenyl, said tetrazolyl and phenyl optionally substituted with one to three groups of R a .

16. The compound according to claim 1 of formula 1 represented by structural formula III:

and pharmaceutically acceptable salts and hydrates thereof.

17. The compound of claim 1 wherein R 1 is selected from the group consisting of CH 3 , or CH 2 OCH 3 , cyclopropyl, cyclobutyl, or optionally substituted phenyl, pyrimidinyl, or pyrazolyl and one of R 4 and R 5 is hydrogen or CH 3 and the other is CH 3 , CH 2 CH 3 , C(CH 3 ) 2 , CH 2 OH, CH(CH 3 )OH, or C(CH 3 ) 2 OH, CN, C(O)OR C(O)N(R) 2 , cyclopropyl, cyclobutyl, cyclopentyl, tetrazolyl, or phenyl, said tetrazolyl and phenyl optionally substituted with one to three groups of R a .

18. The compound of claim 1 wherein both R and R 2 are hydrogen, A is cyclopropyl, cyclobutyl, or cyclopentyl, B is optionally substituted phenyl, or naphthyl, R 1 is selected from the group consisting of CH 3 , CH 2 OCH 3 , cyclopropyl, cyclobutyl, or optionally substituted phenyl, pyrimidinyl, or pyrazolyl and one of R 4 and R 5 is hydrogen and the other is CH 3 , CH 2 CH 3 , C(CH 3 ) 2 , CH 2 OH, CH(CH 3 )OH, or C(CH 3 ) 2 OH, CN, C(O)OR C(O)N(R) 2 , cyclopropyl, cyclobutyl, cyclopentyl, tetrazolyl, or phenyl, said tetrazolyl and phenyl optionally substituted with one to three groups of R a .

19. A compound which is:
2-methyl-6-oxo-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1,6-dihydropyrimidine-4-carboxamide,
2-methyl-6-oxo-N-{1-[4-(trifluoromethyl)phenyl]cyclobutyl}-1,6-dihydropyrimidine-4-carboxamide,
2-(3,4-dimethoxybenzyl)-6-oxo-N-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-1,6-dihydropyrimidine-4-carboxamide,
2-(3,4-dimethoxybenzyl)-6-oxo-N-{(1R)-1-[4(trifluoromethyl)phenyl]ethyl}-1,6-dihydropyrimidine-4-carboxamide,
6-oxo-2-(pyridin-3-ylmethyl)-N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}-1,6-dihydropyrimidine-4-carboxamide,
2-[1-methyl-1-(1H-pyrazol-1-yl)ethyl]-6-oxo-N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}-1,6-dihydropyrimidine-4-carboxamide,
6-oxo-N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}-1,6-dihydropyrimidine-4-carboxamide,
2-methyl-6-oxo-N-{(1R)-1-[4-(trifluoromethoxy)phenyl]ethyl}-1,6-dihydropyrimidine-4

Assignees

• Merck Sharp & Dohme
• Msd R & D (China) Co Ltd

Inventors

• Shen Dong Ming
• Egbertson Melissa
• Berger Richard
• Qian Xiaoxia
• Qian Yimin
• Harper Bart
• Yang Meng
• Guo Zack Zhiqiang
• Rada Vanessa L
• Wang Deping
• Cernak Timothy A
• Sinz Christopher
• Wang Ming
• Wilson Jonathan E
• Xu Shimin

Classifications

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D239/36 Primary

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

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/04

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

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title