INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL

摘要

Novel spirocyclic compounds of formula I: and pharmaceutically acceptable salts thereof are disclosed as inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention. Pharmaceutical compositions and methods of treatment are also included.;

主权项

1. A compound of the formula I:or a pharmaceutically acceptable salt thereof, wherein:
X is R is H, or C1-6alkyl, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents, R′ is H, or C1-6alkyl, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents, R1 is OH, H, CH2OH, or C1-6alkylOC1-6alkyl, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents, or X and R1 together form a bicyclic ring system comprising a saturated carbocyclic ring fused to a heteroaryl ring having 1 N atom, said heteroaryl ring, optionally substituted with 1-4 substitutents independently selected from halo, C1-6alkyl, 3- to 6-membered cycloalkyl, aryl, heteroaryl, CN, or OC1-6 alkyl, wherein alkyl, cycloalkyl, aryl or heteroaryl substituents are further optionally substituted with 1-4 halogen substituents, m is 0, 1, 2, 3, or 4, n is 0, or 1, R2 and R3 are each independently H or C1-6alkyl, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents, or R2 and R3 together form oxo, Y is CH2 or O, R4 is H, C1-6alkyl, or oxo, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents, R5 is H, OH, C1-6alkyl, OC1-6alkyl, OC1-6alkylOC1-6alkyl, or halo, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents, Z is Ra is H, halo, C1-6alkyl, 3- to 6-membered cycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, aryl or heteroaryl substituents are further optionally substituted with 1-4 halogen substituents, Rb is H, C1-6alkyl, or OC1-6alkyl, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents, Rc is C1-6alkyl, or 3- to 6-membered cycloalkyl, wherein alkyl or cycloalkyl substituents are further optionally substituted with 1-4 halogen substituents, and each Rd is independently halo, C1-6alkyl, 3- to 6-membered cycloalkyl, aryl, heteroaryl, CN, or OC1-6 alkyl, wherein alkyl, cycloalkyl, aryl or heteroaryl substituents are further optionally substituted with 1-4 halogen substituents.