Inhibitors of the renal outer medullary potassium channel

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Quick Facts

Patent No.: US 9,493,474
App. No.: 14/353,831
Granted: Nov 15, 2016
Kind: B2

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Abstract

This invention relates to compounds of Formula I having the following general structure: Z 1 —Y 1 —(CH 2 ) n1 —R—(CH 2 ) n2 —Y 2 —Z 2 wherein R represents a fused bicyclic or spirocyclic aliphatic diamine 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.

Claims (77)

1. A compound having structural Formula I:

Z 1 —Y 1 —(CH 2 ) n1 —R—(CH 2 ) n2 —Y 2 —Z 2 I

or a pharmaceutically acceptable salt thereof wherein:

n1 and n2 can be individually either 0 or 1;

R represents a fused bicyclic or spirocyclic aliphatic diamine having one of the following structures:

wherein R-I represents a 9-11-membered saturated bicyclic heterocyclic ring system sharing 1 carbon atom, and R-II represents a 8-10-membered saturated bicyclic heterocyclic ring system sharing 2 carbon atoms, wherein each ring of R-I and each ring of R-II has 1 Nitrogen atom;

R 5 is —H, —F with the proviso that —F is not attached to a carbon that is also attached to nitrogen, —CH 3 , —CF 3 , —CHF 2 , —CH 2 F, or —CH 2 OH, or R 5 represents di-substitution on a single carbon with two of —F with the proviso that —F is not attached to a carbon that is also attached to nitrogen or two of —CH 3 ;

Z 1 is:

Z 2 is:

one of W 1 and W 2 is N and the other is CH;

R 1 and R 2 are each independently —H, —F, —Cl, —Br, cyclopropyl, —C 1-3 alkyl optionally substituted with 1-3 of —F, or —OC 1-3 alkyl optionally substituted with 1-3 of —F;

one of R 3a and R 3b is —CN, tetrazolyl, or —S(O) 2 C (1-3) alkyl and the other is —H, —F, —Cl, —Br, —S—CH 3 , —NH—CH 3 , —O-cyclopropyl, —C 1-3 alkyl optionally substituted with 1-3 of —F, or —OC 1-3 alkyl optionally substituted with 1-3 of —F;

one of R 4a and R 4b is CN, tetrazolyl, or —S(O) 2 C (1-3) alkyl and the other is —H, —F, —Cl, —Br, —S—CH 3 , —NH—CH 3 , —O-cyclopropyl, —C 1-3 alkyl optionally substituted with 1-3 of —F, or —OC 1-3 alkyl optionally substituted with 1-3 of —F;

R a , R aa , R b and R bb are each independently —H, —F, —Cl, —C 1-3 alkyl optionally substituted with 1 to 3 of —F, or —OC 1-3 alkyl optionally substituted with 1 to 3 of —F;

R c and R d are each independently —H, —F, —Cl, —C 1-3 alkyl optionally substituted with 1 to 3 of

F, or —OC 1-3 alkyl optionally substituted with 1 to 3 of —F; and

one of Y 1 or Y 2 is —CH(OH)—; and the other is —CH(OH)—; —C(O)—; or —S(O) 2 —; provided that

where Y 1 or Y 2 is —C(O)— or —S(O) 2 —, then the adjacent n1 or n2, respectively, is 0; and

provided further that where n1 or n2 is 0, the adjacent Y 1 or Y 2 is —C(O)— or —S(O) 2 —.

2. The compound of claim 1 wherein R is:

and R 5 is as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein R is:

and R 5 is as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein:

Z 1 is

and/or Z 2 is