Triazolopyridinone PDE10 inhibitors

1. A compound of the formula I:

wherein:

A is heterocyclyl selected from the group consisting of

(1) imidazolyl, and

(2) quinolinyl;

R 1a , R 1b and R 1c may be absent if the valency of A does not permit such substitution and are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) —(C═O) m —O n —C 1-6 alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R 13 ,

(5) —(C═O) m —O n —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R 13 ,

(6) —(C═O) m —C 2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R 13 ,

(7) —(C═O) m —C 2-4 alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R 13 ,

(8) —(C═O) m —O n -phenyl or —(C═O) m —O n -naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R 13 ,

(9) —(C═O) m —O n -heteroaryl, where the heteraryl is unsubstituted or substituted with one or more substituents selected from R 13 ,

(10) —(C═O) m —NR 10 R 11 , wherein R 10 and R 11 are independently selected from the group consisting of:

(a) hydrogen,

(b) C 1-6 alkyl, which is unsubstituted or substituted with R 14 ,

(c) C 3-6 alkenyl, which is unsubstituted or substituted with R 14 ,

(d) C 3-6 alkynyl, which is unsubstituted or substituted with R 14 ,

(e) C 3-6 cycloalkyl which is unsubstituted or substituted with R 14 ,

(f) phenyl, which is unsubstituted or substituted with R 14 , and

(g) heteroaryl, which is unsubstituted or substituted with R 14 ,

(11) —S(O) 2 —NR 10 R 11 ,

(12) —S(O) q —R 12 , where q is 0, 1 or 2 and where R 12 is selected from the definitions of R 10 and R 11 ,

(13) —CO 2 H,

(14) —CN, and

(15) —NO 2 ;

R 2b is hydrogen

R 2a , and R 2c , are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) —(C═O) m —O n —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents of R 13 ,

(5) —(C═O) m —O n —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R 13 ,

(6) —(C═O) m —C 2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R 13 ,

(7) —(C═O) m —C 2-4 alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R 13 ,

(9) —(C═O) m —O n -heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents selected from R 13 ,

(10) —(C═O) m —NR 10 R 11 ,

(11) —S(O) 2 —NR 10 R 11 ,

(12) —S(O) q —R 12 ,

(13) —CO 2 H,

(14) —CN, and

(15) —NO 2 ;

R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen, and

(3) —C 1-6 alkyl,

or R 3 and R 5 are joined together to form a cyclopropyl ring;

R 13 is selected from the group consisting of:

(1) halogen,

(2) hydroxyl,

(3) —(C═O) m —O n —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R 14 ,

(4) —O n —(C 1-3 )perfluoroalkyl,

(5) —(C═O) m —O n —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R 14 ,

(6) —(C═O) m —C 2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R 14 ,

(7) —(C═O) m —C 2-4 alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R 14 ,

(8) —(C═O) m —O n -phenyl or —(C═O) m —O n -naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R 14 ,

(9) —(C═O) m —O n -heteroaryl, where the heteroaryl is unsubstituted or substituted with one or more substituents selected from R 14 ,

(10) —(C═O) m —NR 10 R 11 ,

(11) —S(O) 2 —NR 10 R 11 ,

(12) —S(O) q —R 12 ,

(13) —CO 2 H,

(14) —CN, and

(15) —NO 2 ;

R 14 is selected from the group consisting of:

(1) hydroxyl,

(2) halogen,

(3) C 1-6 alkyl,

(4) —C 3-6 cycloalkyl,

(5) —O—C 1-6 alkyl,

(6) —O(C═O)—C 1-6 alkyl,

(7) —NH—C 1-6 alkyl,

(8) phenyl,

(9) heteroaryl,

(10) —CO 2 H, and

(11) —CN;

p is 0 or 1, wherein when p is 0 a bond is present;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 of the formula Ia:

Ia

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein A is quinolinyl.

4. The compound of claim 1 wherein A is imidazolyl.

5. The compound of claim 1 wherein R 2b is hydrogen, and R 2a and R 2c are independently selected from the group consisting of:

(1) hydrogen,

(2) chloro,

(3) fluoro,

(4) bromo,

(5) methyl,

(6) isopropoxy,

(7) methoxy,

(8) t-butoxy,

(9) imidazolyl,

(10) isothiazolyl,

(11) oxazolyl,

(12) morpholinyl,

(13) pyrazolyl,

(14) pyridyl,

(15) tetrazolyl, and

(16) thiazolyl.

6. The compound of claim 1 wherein R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, and R 6 is hydrogen.

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

8-bromo-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-bromo-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

6-bromo-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

8-(oxazol-2-yl)-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-(pyridin-4-yl)-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-morpholino-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-(2-hydroxy-1-(4-methoxyphenyl)propan-2-yl)-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3 (2H)-one;

3-oxo-N-(pyridin-3-yl)-2-(2-(quinolin-2-yl)ethyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxamide;

5-bromo-2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)-5-morpholino-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5

8-bromo-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-bromo-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

6-bromo-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

8-(1,3-oxazol-2-yl)-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-pyridin-4-yl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-morpholin-4-yl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-[1-hydroxy-1-(4-methoxyphenyl)ethyl]-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

3-oxo-N-pyridin-3-yl-2-(2-quinolin-2-ylethyl)-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxamide;

6-pyridin-3-yl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-pyridin-3-yl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

8-methyl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-(4-methylphenyl)-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

2-(2-quinolin-2-ylethyl)-5-(1,3-thiazol-5-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-phenyl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-piperidin-1-yl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-[(pyridin-3-ylmethyl)amino]-2-(2-qyinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-(1-hydroxy-1-methylethyl)-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

5-bromo-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl]-5-morpholin-4-yl[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl]-5-pyridin-4-yl[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; and

or a pharmaceutically acceptable salt thereof.

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

9. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use in medicine.