2-pyridyloxy-3-substituted-4-nitrile orexin receptor antagonists

摘要

The present invention is directed to 2-pyridyloxy-3-substituted-4-nitrile compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the 2-pyridyloxy-3-substituted-4-nitrile compounds described herein in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to pharmaceutical compositions comprising these compounds. The present invention is also directed to uses of these pharmaceutical compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

主权项

1. A compound of the formula I: wherein: A is selected from the group consisting of phenyl, naphthyl and heteroaryl; R1a, R1b and R1c are independently selected from the group consisting of:
(1) hydrogen,(2) halogen,(3) hydroxyl,(4) —(C═O)m—On—C1-6alkyl, 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 R4,(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R4,(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more sub stituents selected from R4,(7) —(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R4,(8) —(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R4,(9) —(C═O)m—On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R4,(10) —(C═O)m—NR10R11, wherein R10 and R11 are independently selected from the group consisting of:
(a) hydrogen,(b) C1-6alkyl, which is unsubstituted or substituted with R4,(c) C3-6alkenyl, which is unsubstituted or substituted with R4,(d) C3-6alkynyl, which is unsubstituted or substituted with R4,(e) C3-6cycloalkyl which is unsubstituted or substituted with R4,(f) phenyl, which is unsubstituted or substituted with R4, and(g) heterocycle, which is unsubstituted or substituted with R4,(11) —S(O)2—NR10R11,(12) —S(O)q—R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of R10 and R11,(13) —CO2H,(14) —CN, and(15) —NO2; R3 is selected from C1-6alkyl and C3-6cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R4; R4 is selected from the group consisting of:
(1) hydroxyl,(2) halogen,(3) C1-6alkyl,(4) —C3-6cycloalkyl,(5) —O—C1-6alkyl,(6) —O(C═O)—C1-6alkyl,(7) —NH2,(7) —NH—C1-6alkyl,(8) —NO2,(9) phenyl,(10) heterocycle,(11) —CO2H, and(12) —CN; R5 is selected from the group consisting of:
(1) halogen,(2) hydroxyl,(3) C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,(4) C3-6cycloalkyl, which is unsubstituted or substituted with C1-6alkyl, halogen, hydroxyl or phenyl,(5) —O—C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, and(6) —S—C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl; or a pharmaceutically acceptable salt thereof.