Isoxazolopyridine orexin receptor antagonists

1. A compound of the formula If:

wherein:

A 3 is selected from the group consisting of phenyl, naphthyl, C 3-6 cycloalkyl, —NR 10 R 11 and heterocycle;

R 1a is 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 -napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R 13 ,

(9) —(C═O) m —O n -heterocycle, where the heterocycle 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) heterocycle, 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 2a and R 2b 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 selected from R 13 ,

(5) —(C═0) 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 -napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R 13 ,

(9) —(C═O) m —O n -heterocycle, where the heterocycle 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 3a , R 3b and R 3c may be absent if the valency of A 3 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 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 -napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R 13 ,

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

(9) —(C═O) m —O n -heterocycle, where the heterocycle 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) heterocycle,

(10) —CO 2 H, and

(11) —CN;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein A 3 is selected from the group consisting of:

(1) phenyl,

(2) pyridine,

(3) pyrazolyl,

(4) pyrazinyl, and

(5) thiophenyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1a is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl or napthyl,

(5) —O—C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(6) heteroaryl, wherein heteroaryl is selected from triazolyl, oxazolyl and pyrimidinyl, which is unsubstituted or substituted with halogen, hydroxyl or C 1-6 alkyl, and

(7) phenyl, which is unsubstituted or substituted with halogen, hydroxyl or C 1-6 alkyl.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein R 1a is selected from the group consisting of:

(1) hydrogen,

(2) chloro,

(3) fluoro,

(4) methyl,

(5) triazolyl,

(6) oxazolyl,

(7) pyrimidinyl, and

(8) phenyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(5) —O—C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, and

(6) —NH—C 1-6 alkyl, or —N(C 1-6 alkyl)(C 1-6 alkyl), which is unsubstituted or substituted with halogen.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are independently selected from the group consisting of:

(1) hydrogen,

(2) fluoro,

(3) methoxy, and

(4) trifluoromethyl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 3a , R 3b and R 3c are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl or napthyl, and

(5) —O—C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein R 3a , R 3b and R 3c are independently selected from the group consisting of:

(1) hydrogen,

(2) chloro,

(3) fluoro, and

(4) methyl.

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

N-[(5,6-dimethoxy-3-methylpyridin-2-yl)methyl]-6-(5-methylpyridin-3-yl)-3-(thiophen-2-yl)isoxazolo[5,4-b]pyridine-4-carboxamide;

6-(5-bromopyridin-3-yl)-N-[(5,6-dimethoxypyridin-2-yl)methyl]-3-phenylisoxazolo[5,4-b]pyridine-4-carboxamide;

N-[(5,6-dimethoxypyridin-2-yl)methyl]-6-(5-methylpyridin-3-yl)-3-phenylisoxazolo[5,4-b]pyridine-4-carboxamide;

N-[(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]-6-(5-methylpyridin-3-yl)-3-phenylisoxazolo[5,4-b]pyridine-4-carboxamide;

N-[(5,6-dimethoxypyrazin-2-yl)methyl]-6-(5-methylpyridin-3-yl)-3-phenylisoxazolo[5,4-b]pyridine-4-carboxamide;

N-(3,4-dimethoxybenzyl)-6-(5-methylpyridin-3-yl)-3-phenylisoxazolo[5,4-b]pyridine-4-carboxamide;

N-[2-(5,6-dimethoxypyridin-2-yl)ethyl]-6-(5-methylpyridin-3-yl)-3-phenylisoxazolo[5,4-b]pyridine-4-carboxamide;

N-[(5,6-dimethoxypyridin-2-yl)methyl]-6-(5-methylpyridin-3-yl)-3-(pyridin-4-yl)isoxazolo[5,4-b]pyridine-4-carboxamide;

3-(3-chlorophenyl)-N-[(5,6-dimethoxypyridin-2-yl)methyl]-6-(5-methylpyridin-3-yl)isoxazolo[5,4-b]pyridine-4-carboxamide;

N-[(5,6-dimethoxypyridin-2-yl)methyl]-6-(5-methylpyridin-3-yl)-3-(thiophen-2-yl)isoxazolo[5,4-b]pyridine-4-carboxamide;

N-[(5,6-dimethoxypyridin-2-yl)methyl]-6-(5-methylpyridin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)isoxazolo[5,4-b]pyridine-4-carboxamide;

3-(4-chlorophenyl)-N-[(5,6-dimethoxypyridin-2-yl)methyl]-6-(5-methylpyridin-3-yl)isoxazolo[5,4-b]pyridine-4-carboxamide;

N-[(5,6-dimethoxypyridin-2-yl)methyl]-3-(4-fluorophenyl)-6-(5-methylpyridin-3-yl)isoxazolo[3,4-b]pyridine-4-carboxamide;

N-[(5,6-dimethoxypyridin-2-yl)methyl]-6-(5-methylpyridin-3-yl)-3-(pyrazin-2-yl)isoxazolo[5,4-b]pyridine-4-carboxamide;

N-[(5,6-dimethoxy-3-methylpyridin-2-yl)methyl]-6-(5-methylpyridin-3-yl)-3-(thiophen-2-yl)isoxazolo[5,4-b]pyridine-4-carboxamide; and

6-(5-bromopyridin-3-yl)-N-[(5,6-dimethoxypyridin-2-yl)methyl]-3-(thiophen-2-yl)isoxazolo[5,4-b]pyridine-4-carboxamide;

or a pharmaceutically acceptable salt thereof.

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

11. A method for enhancing the quality of sleep in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

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