Inhibitors of the renal outer medullary potassium channel
View Patent ↗This invention relates to compounds having structural Formula I: and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kir1.1). The compounds of Formula I 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.
1. A compound having structural Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
B 1 —Z B — is B 1 —CHR 1 CH 2 —, B 1 —CHR 1 C(O)—, B 1 —C(O)—, B 1 —CHR 1 CH 2 C(O)—, B 1 —OCH 2 C(O)—, or B 1 —CH(CH 2 OH)—;
—Z A -A 1 is CHR 21 CR 2 R 22 -A 1 , —CH═CR 2 -A 1 , —C≡C-A 1 , —S-A 1 , —CH 2 O-A 1 , —C(O)CHR 2 -A 1 , —O-A 1 , —NHCHR 2 -A 1 , —CH 2 N(CH 3 )CH 2 CH(OH)-A 1 , —CH 2 N(CH 3 )CH(CH 2 OH)-A 1 , —CH 2 N(CH 3 )-A 1 , —CH 2 S-A 1 , —CH 2 O-A 1 , CH 2 S(O)-A 1 , —CH 2 S(O 2 )-A 1 , or —NH-A 1 ;
A 1 is
B 1 is
X is O or S;
R 1 is —H, —C 1-6 alkyl, —C 3-6 cycloalkyl, CF 3 , —OH, F, —CH 2 OH, —C(O)OH, —C(O)OC 1-6 alkyl, or R 1 may be joined with R 13b by 2-3 carbon atoms or 1-2 carbon atoms and one heteroatom to form a ring;
R 2 is —H, —C 1-6 alkyl, —C 3-6 cycloalkyl, CF 3 , —OH, F, —CH 2 OH, —C(O)OH, —C(O)OC 1-6 alkyl, or R 2 may be joined with R 13a by 2-3 carbon atoms or 1-2 carbon atoms and one heteroatom to form a ring;
R 4 is H, —OH, F, —O—C 1-6 alkyl, or —C 1-6 alkyl, or may be joined with R 5 by a bond, or by 1-4 carbon atoms, to form a ring;
R 5 is H, —OH, F, —O—C 1-6 alkyl, or —C 1-6 alkyl, or may be joined with R 4 by a bond, or by 1-4 carbon atoms to form a ring;
R 6 is H, —C(O)OCH 3 , C(O)OCH 2 CH 3 , —OC(O)CH 3 —CH 2 OH, —OH, —CHF 3 , —N(CH 3 ) 2 , —CH 3 , —C 6 H 5 , or F;
R 13a is —H, —C 1-6 alkyl, —C 3-6 cycloalkyl, -halogen, CF 3 , —CH 2 OH, —CO 2 R 16a , —OR 16a , —SR 16a , —CN, -aryl, -heterocycle, —NR 16a R 18a , or R 13a may be joined with R 2 by 2-3 carbon atoms or 1-2 carbon atoms and one heteroatom to form a ring, or R 13a may be joined with R 14a by 3-4 carbon atoms or 2-3 carbon atoms and one heteroatom to form a ring;
R 13b is —H, —C 1-6 alkyl, —C 3-6 cycloalkyl, -halogen, CF 3 , —CH 2 OH, —CO 2 R 16b , —OR 16b , —SR 16b , —CN, -aryl, -heterocycle, —NR 16b R 18b , or R 13b may be joined to R 1 by 2-3 carbon atoms or 1-2 carbon atoms and one heteroatom to form a ring, or R 13b may be joined to R 14b by 3-4 carbon atoms or 2-3 carbon atoms and one heteroatom to form a ring;
R 14a is —H, —C 1-6 alkyl, —C 3-6 cycloalkyl, -halogen, CF 3 , —CH 2 OH, —CO 2 R 17a , —OR 17a , —SR 17a , —CN, -aryl, -heterocycle, or R 14a may be joined to R 13a by 3-4 carbon atoms or 2-3 carbon atoms and one heteroatom to form a ring;
R 14b is —H, —C 1-6 alkyl, —C 3-6 cycloalkyl, -halogen, CF 3 , —CH 2 OH, —CO 2 R 17b , —OR 17b , —SR 17b , —CN, -aryl, -heterocycle, or R 14b may be joined to R 13b by 3-4 carbon atoms or 2-3 carbon atoms and one heteratom to form a ring;
R 15a is —H, halogen, —C 1-6 alkyl, C 3-6 cycloalkyl, —OC 1-6 alkyl, or —CF 3 ;
R 15b is —H, halogen, —C 1-6 alkyl, C 3-6 cycloalkyl, —OC 1-6 alkyl, or —CF 3 ;
R 16a , R 16b , R 17a , R 17b , R 18a , and R 18b are independently —H, —C 1-6 alkyl, or —C 3-6 cycloalkyl;
R 19 and R 20 are H, or may be joined by a bond or 1-2 carbon atoms, to form a 4-5-membered ring; and
R 21 and R 22 are H, or, together with carbon atom to which they are attached, form —C 3-6 cycloalkyl.
2. A compound of claim 1 , wherein
or a pharmaceutically acceptable salt thereof.
3. A compound of claim 1 , wherein, R 13a is H, F, Br, Cl, CH 3 , or —OCH 3 ; R 14a is H or F; and R 15a is H or CH 3 , or a pharmaceutically acceptable salt thereof.
4. A compound of claim 3 , wherein, R 13a is H or CH 3 , or a pharmaceutically acceptable salts thereof.
5. A compound of claim 1 , wherein R 13b is H, F, Br, Cl, —CF 3 , —CH 3 or —OCH 3 ; R 14b is H or Cl; and R 15b is H or F, or a pharmaceutically acceptable salt thereof.
6. A compound of claim 1 , wherein, where B 1 —Z B — is B 1 —CH 2 CH 2 —, B 1 —CHR 1 C(O)—, B 1 —C(O)—, B 1 —CH 2 CH 2 C(O)—, B 1 —OCH 2 C(O)—, B 1 —CH(OH)CH 2 —, or B 1 —CH(CH 2 OH)—, or a pharmaceutically acceptable salts thereof.
7. A compound of claim 6 , wherein, B 1 —Z B — is B 1 —CH 2 CH 2 —, B 1 —CHR 1 C(O)— or B 1 —CH(OH)CH 2 —, or a pharmaceutically acceptable salts thereof.
8. A compound of claim 1 , wherein —Z A -A 1 is —CHR 21 CR 2 R 22 -A 1 , —CH═CH-A 1 , —S-A 1 , —CH 2 O-A 1 , —C(O)CH 2 -A 1 , —O-A 1 , —CH 2 CH(OH)-A 1 , —NHCH 2 -A 1 , —CH 2 N(CH 3 )CH 2 CH(OH)-A 1 , —CH 2 N(CH 3 )CH(CH 2 OH)-A 1 , —CH 2 N(CH 3 )-A 1 , —CH 2 S-A 1 ,
—CH 2 O-A 1 , CH 2 S(O)-A 1 , —CH 2 S(O) 2 -A 1 , or —NH-A 1 , or a pharmaceutically acceptable salt thereof.
9. A compound of claim 8 , wherein, —Z A -A 1 is —CH 2 CH 2 -A 1 , —CH 2 O-A 1 , or —CH 2 CH(OH)-A 1 , or a pharmaceutically acceptable salt thereof.
10. A compound of claim 1 , which is
5-[(E)-2-{1-[(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetyl]piperidin-4-}ethenyl]-2-benzofuran-1(3H)-one,
5-(2-{1-[(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetyl]piperidin-4-yl}ethyl)-2-benzofuran-1(3H)-one,
5-[(1-{[(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)oxy]acetyl}piperidin-4-yl)oxy]-2-benzofuran-1(3H)-one,
5-({1-[2-hydroxy-2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperidin-4-yl}sulfanyl)-2-benzofuran-1(3H)-one,
5-[(1R)-1-Hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperidin-1-yl}ethyl]-4-methyl-2-benzofuran-1(3H)-one,
5-[(1R)-1-Hydroxy-2-{4-[1-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperidin-1-yl}ethyl]-4-methyl-2-benzofuran-1(3H)-one,
4-Methyl-5-[2-(4-{[(1-oxo-1,3-dihydro-2-benzofuran-5-yl)methyl]amino}piperidin-1-yl)ethyl]-2-benzofuran-1(3H)-one,
5-{(1R)-1-Hydroxy-2-[4-({[(2R)-2-hydroxy-2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl](methyl)amino}methyl)piperidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one,
5-{(1R)-1-Hydroxy-2-[4-({[2-hydroxy-1-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl](methyl)amino}methyl)piperidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one,
5-[({1-[(2R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperidin-4-yl}methyl)sulfanyl]-4-methyl-2-benzofuran-1(3H)-one,
5-({1-[(2R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperidin-4-yl}methoxy)-4-methyl-2-benzofuran-1(3H)-one,
5-[({1-[(2R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperidin-4-yl}methoxy)-4-methyl-2-benzofuran-1(3H)-one,
5-[(1-[2-Hydroxy-1-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperidin-4-yl}methyl)sulfinyl]-4-methyl-2-benzofuran-1(3H)-one,
5-({1-[(2R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperidin-4-yl}methyl)sulfonyl]-4-methyl-2-benzofuran-1(3H)-one,
or a pharmaceutically acceptable salt thereof.
11. A composition comprised of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.