INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL

摘要

This invention relates to compounds of Formula I-VI having the following general structure:;Z1—Y1—(CH2)n1—R—(CH2)n2—Y2—Z2 ;wherein R is a 6-8 membered saturated heterocyclic ring having 2 Nitrogen atoms connected with —(CH2)n1— and —(CH2)n2—, respectively, and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kir1.1). The compounds are useful as diuretics and natriuretics and therefore are useful for the therapy and prophylaxis of disorders resulting from excessive salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure.

主权项

1. A compound having structural Formula I: or a pharmaceutically acceptable salt thereof wherein the central ring system is a saturated heterocyclic ring, and wherein: n1 and n2 can be individually either 0 or 1; a is —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2OCH2— or absent; wherein the —CH2— is optionally substituted with 1-2 of —F, and wherein the —CH2CH2—, —CH2CH2CH2—, or —CH2OCH2— is optionally substituted with 1-3 of —F; b is —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2OCH2— or absent; wherein the —CH2— is optionally substituted with 1-2 of —F, and wherein the —CH2CH2—, —CH2CH2CH2—, or —CH2OCH2— is optionally substituted with 1-3 of —F; c is —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2OCH2— or absent; wherein the —CH2— is optionally substituted with 1-2 of —F, and wherein the —CH2CH2—, —CH2CH2CH2—, or —CH2OCH2— is optionally substituted with 1-3 of —F; wherein at least one of a, b, or c is absent; R5 and R6 are individually either —C1-3 alkyl optionally substituted with 1-3 of —F, or together they form C3-6 cycloalkyl optionally substituted with 1-3 of —F; Z1 is: Z2 is: one of W1 and W2 is N and the other is CH; R1 and R2 are each independently —H, —F, —Cl, —Br, cyclopropyl, —C1-3alkyl optionally substituted with 1-3 of —F, or —OC1-3alkyl optionally substituted with 1-3 of —F; one of R3a and R3b is —CN, tetrazolyl, or —S(O)2C1-3alkyl and the other is —H, —F, —Cl, —Br, —S—CH3, —NH—CH3, —O-cyclopropyl, —C1-3alkyl optionally substituted with 1-3 of —F, or —OC1-3alkyl optionally substituted with 1-3 of —F; one of R4a and R4b is CN, tetrazolyl, or —S(O)2C1-3alkyl and the other is —H, —F, —Cl, —Br, —S—CH3, —NH—CH3, —O-cyclopropyl, —C1-3alkyl optionally substituted with 1-3 of —F, or —OC1-3alkyl optionally substituted with 1-3 of —F; R3c and R4c are each independently —H, —C1-6alkyl or —C1-6cycloalkyl; Ra, Raa, Rb and Rbb are each independently —H, —F, —Cl, —C1-3alkyl optionally substituted with 1 to 3 of —F, or —OC1-3alkyl optionally substituted with 1 to 3 of —F; Rc and Rd are each independently —H, —F, —Cl, —C1-3alkyl optionally substituted with 1 to 3 of —F, or —OC1-3alkyl optionally substituted with 1 to 3 of —F; and one of Y1 or Y2 is —CH(OH)—; and the other is —CH(OH)—; —C(O)—; —S(O)2—; —CH2— or absent; provided that where Y1 or Y2 is —C(O)—; —S(O)2— or absent, then the adjacent n1 or n2, respectively, is 0; and provided further that where n1 or n2 is 0, the adjacent Y1 or Y2 is —C(O)—, —S(O)2— or absent.