TRIAZOLOPYRIDINONE PDE10 INHIBITORS

摘要

The present invention is directed to triazolopyridinone 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.

主权项

1. A compound of the formula I: wherein: A is heterocyclyl; R1a, R1b and R1c 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—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 R13,(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,(7) —(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,(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 R13,(9) —(C═O)m—On-heteroaryl, where the heteraryl is unsubstituted or substituted with one or more substituents selected from R13,(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 R14,(c) C3-6alkenyl, which is unsubstituted or substituted with R14,(d) C3-6alkynyl, which is unsubstituted or substituted with R14,(e) C3-6cycloalkyl which is unsubstituted or substituted with R14,(f) phenyl, which is unsubstituted or substituted with R14, and(g) heteroaryl, which is unsubstituted or substituted with R14,(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; R2a, R2b and R2c are independently selected from the group consisting of:
(1) hydrogen,(2) halogen,(3) hydroxyl,(4) —(C═O)m—On—C1-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,(7) —(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,(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 R13,(9) —(C═O)m—On-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents selected from R13,(10) —(C═O)m—NR10R11,(11) —S(O)2—NR10R11,(12) —S(O)q—R12,(13) —CO2H,(14) —CN, and(15) —NO2; R3, R4, R5 and R6 are independently selected from the group consisting of:
(1) hydrogen,(2) halogen, and(3) —C1-6alkyl,or R3 and R5 are joined together to form a cyclopropyl ring; R13 is selected from the group consisting of:
(1) halogen,(2) hydroxyl,(3) —(C═O)m—On—C1-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R14,(4) —On—(C1-3)perfluoroalkyl,(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R14,(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R14,(7) —(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R14,(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 R14,(9) —(C═O)m—On-heteroaryl, where the heteroaryl is unsubstituted or substituted with one or more substituents selected from R14,(10) —(C═O)m—NR10R11,(11) —S(O)2—NR10R11,(12) —S(O)q—R12,(13) —CO2H,(14) —CN, and(15) —NO2; R14 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) —NH—C1-6alkyl,(8) phenyl,(9) heteroaryl,(10) —CO2H, and(11) —CN; p is 0 or 1, wherein when p is 0 a bond is present; or a pharmaceutically acceptable salt thereof.