IP Library › Granted Patent US 9,273,033

Granted Patent B2

US 9,273,033 · App. 14/443,624 · Granted Mar 1, 2016

Substituted pyridone derivatives as PDE10 inhibitors

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,273,033
App. No.: 14/443,624
Granted: Mar 1, 2016
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention is directed to substituted pyridinone compounds which are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 10 (PDE10). The present invention also relates to the use of such compounds for treating neurological and psychiatric disorders, such as schizophrenia, psychosis or Huntington's disease, and those associated with striatal hypofunction or basal ganglia dysfunction.

Claims (194)

1. A compound of the formula I:

wherein:

A is selected from the group consisting of:

(1) pyridyl,

(2) quinolinyl,

(3) cyclopentapyridinyl;

(4) tetrahydroquinolinyl

said pyridyl, quinolinyl, cyclopentapyridinyl, and tetrahydroquinolinyl optionally substituted with 1 to 3 groups of R a

R 4 is selected from the group consisting of:

(1) pyridinone,

(2) pyridazinone,

(3) pyrazinone,

(4) pyrimidinone, and

(5) dihydroindolizinone

said pyridinone, pyridazinone, pyrimidinone, pyrazinone, dihydroindolizinone optionally substituted with 1 to 3 groups of R a,

R a selected from the group consisting of:

(1) (CH 2 ) n C 1-4 , haloalkyl, said alkyl optionally substituted with one to three groups of OH,

(2) halogen,

(3) (CH 2 ) n OR,

(4) C 1-6 alkyl, said alkyl optionally substituted with one to three groups of OH

(5) (CH 2 ) n C 3-6 cycloalkyl,

(6) (CH 2 ) n C 6-10 aryl,

(7) —(CH 2 ) n CO 2 R,

(8) —(CH 2 ) n CN,

(9) S(O) p R

(10) C 2-6 alkenyl;

R is selected from the group consisting of:

(1) hydrogen, and

(2) C 1-6 alkyl, said alkyl optionally substituted with one to three groups of OH,

n is 0, 1, 2, 3, or 4,

p is 0, 1, or 2,

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein A is an optionally substituted pyridyl.

3. The compound according to claim 1 wherein A is an optionally substituted quinolinyl.

4. The compound according to claim 1 wherein R 4 is optionally substituted pyridinone.

5. The compound according to claim 1 wherein R 4 is optionally substituted dihydroindolizinone.

6. The compound according to claim 4 wherein the pyridinone is represented by structural formula A or B:

7. The compound according to claim 1 wherein R 4 is optionally substituted pyridazinone.

8. The compound according to claim 1 wherein R 4 is optionally substituted pyrazinone or dihydroindolizinone.

9. The compound according to claim 1 wherein R 4 is optionally substituted pyrimidinone.

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

or a pharmaceutically acceptable salt thereof wherein R 4 is selected from the group consisting of optionally substituted pyridinone, pyridazinone, pyrazinone, pyrimidinone or dihydroindolizinone, said pyridinone, pyridazinone, pyrazinone, pyrimidinone and dihydroindolizinone optionally substituted with 1 to 3 groups selected from the group consisting of OH, (CH 2 ) 2 OCH 3 ,(CH 2 ) 1-2 OH, OCH(CH 3 ) 2 , halogen, CF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , OCH 3 , (CH 2 ) 0-1 COOH, (CH 2 ) 0-1 COO(CH 2 ) 1-2 CH 3 , (CH 2 ) 0-2 CN, CHCH 3 OH, OCH 2 CH 3 , C(CH 3 )OH, SCH 3 , SCH 3 , SO 2 CH 3 , S(O)CH 3 , CH(CF 2 )OH, OCH(CH 2 ) 2 OH, CH(CF 3 )OH, methyl, ethyl, propyl, propylene, (CH 2 ) 0-1 cyclopropyl, and phenyl.

11. The compound according to claim 10 wherein R 4 is optionally substituted pyridinone.

12. The compound according to claim 1 represented by structural formula Ib:

or a pharmaceutically acceptable salt thereof wherein R 4 is selected from the group consisting of optionally substituted pyridinone, pyridazinone, pyrazinone, pyrimidinone and dihydroindolizinone, said pyridinone, pyridazinone, pyrazinone, pyrimidinone or dihydroindolizinone optionally substituted with 1 to 3 groups selected from the group consisting of OH, (CH 2 ) 2 OCH 3 ,(CH 2 ) 1-2 OH, OCH(CH 3 ) 2 , halogen, CF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , OCH 3 , (CH 2 ) 0-1 COOH, (CH 2 ) 0-1 COO(CH 2 ) 1-2 CH 3 , (CH 2 ) 0-2 CN, CHCH 3 OH, OCH 2 CH 3 , C(CH 3 )OH, SCH 3 , SCH 3 , SO 2 CH 3 , S(O)CH 3 , CH(CF 2 )OH, OCH(CH 2 ) 2 OH, CH(CF 3 )OH, methyl, ethyl, propyl, propylene, (CH 2 ) 0-1 cyclopropyl, and phenyl.

13. The compound according to claim 1 represented by structural formula Ic:

or a pharmaceutically acceptable salt thereof wherein R4 is selected from the group consisting of optionally substituted pyridinone, pyridazinone, pyrazinone, pyrimidinone or dihydroindolizinone, said pyridinone, pyridazinone, pyrazinone, pyrimidinone or dihydroindolizinone optionally substituted with 1 to 3 groups selected from the group consisting of OH, (CH 2 ) 2 OCH 3 ,(CH 2 ) 1-2 OH, OCH(CH 3 ) 2 , halogen, CF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , OCH 3 , (CH 2 ) 0-1 COOH, (CH 2 ) 0-1 COO(CH 2 ) 1-2 CH 3 , (CH 2 ) 0-2 CN, CHCH 3 OH, OCH 2 CH 3 , C(CH 3 )OH, SCH 3 , SCH 3 , SO 2 CH 3 , S(O)CH 3 , CH(CF 2 )OH, OCH(CH 2 ) 2 OH, CH(CF 3 )OH, methyl, ethyl, propyl, propylene, (CH 2 ) 0-1 cyclopropyl, and phenyl.

14. The compound according to claim 1 wherein A is optionally substituted tetrahydroquinolinyl and R4 is selected from the group consisting of optionally substituted pyridinone, pyridazinone, pyrazinone, pyrimidinone or dihydroindolizinone, said pyridinone, pyridazinone, pyrazinone, pyrimidinone or dihydroindolizinone optionally substituted with 1 to 3 groups selected from the group consisting of OH, (CH 2 ) 2 OCH 3 ,(CH 2 ) 1-2 OH, OCH(CH 3 ) 2 , halogen, CF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , OCH 3 , (CH 2 ) 0-1 COOH, (CH 2 ) 0-1 COO(CH 2 ) 1-2 CH 3 , (CH 2 ) 0-2 CN, CHCH 3 OH, OCH 2 CH 3 , C(CH 3 )OH, SCH 3 , SCH 3 , SO 2 CH 3 , S(O)CH 3 , CH(CF 2 )OH, OCH(CH 2 ) 2 OH, CH(CF 3 )OH, methyl, ethyl, propyl, propylene, (CH 2 ) 0-1 cyclopropyl, and phenyl, or a pharmaceutically acceptable salt thereof.

15. A compound which is selected from the group consisting of:

(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)-2-oxopyridin-1(2H)-yl)acetate,

5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

1,6-dimethyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-ethyl-6-methyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

1-ethyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-(2-methoxyethyl)-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

1-(2-methoxyethyl)-6-methyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)-methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-methoxy-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-isopropyl-5-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

5-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)-1-phenylpyridin-2(1H)-one,

1-(difluoromethyl)-5-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-methoxy-5-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-isopropyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-(difluoromethyl)-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)-1-phenylpyridin-2(1H)-one,

3-ethyl-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

1-isopropyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

3-methoxy-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

3-fluoro-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-phenylpyridin-2(1H)-one,

1-(difluoromethyl)-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

1-isopropyl-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

1-methoxy-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

1-cyclopropyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

1-ethyl-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

3-fluoro-1-methyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

3-fluoro-1-methyl-5-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1,6-dimethylpyridin-2(1H)-one,

1-methyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-methyl-5-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-(2-methoxyethyl)-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-6-methylpyridin-2(1H)-one,

1-(2-methoxyethyl)-6-methyl-5-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

1-ethyl-5-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-ethyl-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-6-methylpyridin-2(1H)-one,

1,6-dimethyl-5-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-ethyl-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-3-methylpyridin-2(1H)-one,

1-ethyl-6-methyl-5-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-isopropyl-6-methyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1,3-dimethylpyridin-2(1H)-one,

1-(2-methoxyethyl)-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

1,3-dimethyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-ethyl-3-methyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

5-(4-(((1S,2S)-2-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

1-(2,2-difluoroethyl)-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

1-(2,2-difluoroethyl)-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

3-(5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2-oxopyridin-1(2H)-yl)propanenitrile,

3-(5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)-2-oxopyridin-1(2H)-yl)propanenitrile,

methyl 2-(5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2-oxopyridin-1(2H)-yl)acetate,

1-methyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-(cyclopropylmethyl)-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

2-(5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)-2-oxopyridin-1(2H)-yl)acetonitrile,

5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one,

1-(cyclopropylmethyl)-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

5-(4-(((1S,2S)-2-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-3-methoxy-1-methylpyridin-2(1H)-one,

3-ethyl-1-methyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

3-methoxy-1-methyl-5-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

3-methoxy-1-methyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

5-(4-(((1S,2S)-2-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1,6-dimethylpyridin-2(1H)-one,

1,6-dimethyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile,

5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile,

5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyrazin-2(1H)-one,

1-methyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyrazin-2(1H)-one,

6-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridazin-3(2H)-one,

6-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2-methylpyridazin-3(2H)-one,

2,4-dimethyl-6-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridazin-3(2H)-one,

6-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2,4-dimethylpyridazin-3(2H)-one,

6-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2,5-dimethylpyridazin-3(2H)-one,

2,5-dimethyl-6-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridazin-3(2H)-one,

1-ethyl-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

5-methyl-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1,5-dimethyl-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

5-chloro-4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

1,5-dimethyl-4-(2-methyl-4-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

5-methyl-4-(2-methyl-4-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1,5-dimethyl-4-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-5-methylpyridin-2(1H)-one,

1-methyl-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-methyl-4-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-methyl-4-(2-methyl-4-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

5-methyl-4-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1,5-dimethylpyridin-2(1H)-one,

5-chloro-4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

4-(4-(((1R,2R)-2-(5-fluoropyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

1-(2-methoxyethyl)-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

1,6-dimethyl-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1,6-dimethylpyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(5-fluoropyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile,

4-(4-(((1S,2S)-2-(5-(difluoromethoxy)pyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

1-isopropyl-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methyl-5-(methylthio)pyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methyl-5-(trifluoromethyl)pyridin-2(1H)-one,

4-(4-(((1R,2R)-2-(5-(difluoromethoxy)pyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

1-ethyl-4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

1-ethyl-4-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1,6-dimethyl-4-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methyl-5-(methylsulfonyl)pyridin-2(1H)-one,

5-chloro-1-methyl-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

1-(2-methoxyethyl)-4-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-(2-methoxyethyl)-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

5-chloro-1-methyl-4-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

4-(4-(((1R,2R)-2-(5-chloropyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile,

4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one,

1-(2,2-difluoroethyl)-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

ethyl 4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methyl-5-(methylsulfinyl)pyridin-2(1H)-one, R or S,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methyl-5-(methylsulfinyl)pyridin-2(1H)-one, S or R,

2-(4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2-oxopyridin-1(2H)-yl)acetonitrile,

3-(4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2-oxopyridin-1(2H)-yl)propanenitrile,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1,6-dimethylpyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methyl-3-(methylthio)pyridin-2(1H)-one,

1-(difluoromethyl)-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

1-(difluoromethyl)-4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

1-(2-methoxyethyl)-4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

3-(4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)-2-oxopyridin-1(2H)-yl)propanenitrile,

2-(4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)-2-oxopyridin-1(2H)-yl)acetonitrile,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one,

1-allyl-4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

1-allyl-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

methyl 2-(4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2-oxopyridin-1(2H)-yl)acetate,

1-methyl-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridin-2(1H)-one,

1-(2-hydroxyethyl)-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

1-(2-hydroxyethyl)-4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

methyl 2-(4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)-2-oxopyridin-1(2H)-yl)acetate,

1-(2,2-difluoroethyl)-4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)pyridin-2(1H)-one,

4-(4-(((1S,2S)-2-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1,5-dimethylpyridin-2(1H)-one,

5-cyclopropyl-4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-1-methylpyridin-2(1H)-one,

1-cyclopropyl-4-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)-pyrimidin-5-yl)pyridin-2(1H)-one,

2-(4-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2-oxopyridin-1(2H)-yl)acetic acid,

2-methyl-5-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyridazin-3(2H)-one,

5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2-methylpyridazin-3(2H)-one,

4-chloro-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2-methylpyridazin-3(2H)-one,

6-methoxy-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2-methylpyridazin-3(2H)-one,

6-hydroxy-5-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-2-methylpyridazin-3(2H)-one,

3-methyl-6-(2-methyl-4-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyrimidin-4(3H)-one,

3-methyl-6-(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)pyrimidin-4(3H)-one,

6-(4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidin-5-yl)-3-methylpyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

17. A method for treating anxiety in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

Assignments (2)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 16, 2015

From: MCCOMAS, CASEY C.; KUDUK, SCOTT D.; REGER, THOMAS S.

To: MERCK SHARP & DOHME CORP.

Reel/Frame 037051/0047 →