Compounds, compositions and methods
Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
1. At least one chemical entity chosen from compounds of Formula I
and pharmaceutically acceptable salts thereof, wherein
T is —O—;
W, X, Y, and Z are —C═;
R 1 is selected from optionally substituted
optionally substituted
optionally substituted
and optionally substituted
R 2 is optionally substituted pyridin-3-yl;
R 3 is hydrogen;
R 4 is fluoro;
R 5 is hydrogen;
R 6 and R 7 are hydrogen;
R 13 is hydrogen.
2. At least one chemical entity of claim 1 where R 1 is
each of which is substituted with one or more lower alkyl groups.
3. At least one chemical entity of claim 2 where R 1 is
4. At least one chemical entity of claim 1 wherein R 2 pyridin-3-yl optionally substituted with lower alkyl.
5. At least one chemical entity of claim 1 wherein the compound of Formula I is chosen from yloxy))-5-fluorophenyl](3-pyridylamino)carboxamide;
N-[3-((2S,7 a S)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizin-2-yloxy))-5-fluorophenyl](3-pyndylamino)carboxamide;
N-[3-((2Rg7 a R)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizin-2-yloxy))-5-fluorophenyl](3-pyridylamino)carboxamide;
N-[3-((7 a S,2R)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizin-2-yloxy))-5-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide;
N-[3-((1S,7 a R)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizinyloxy))-5-fluorophenyl](3-pyridylainino)carboxamide;
N-[3-((1S,7 a R)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizinyloxy))-5-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide;
N-[3-(2,6,-dimethyl-1,1-dioxo(1,2,6-thiadiazaperhydroin-4-yloxy))-5-fluorophenyl](3-pyridylamino)carboxamide;
N-[3-(2,6-dimethyl-1,1-dioxo(1,2,6-thiadiazaperhydroin-4-yloxy))-5-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide;
N-[3-((2R,7 a R)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizin-2-yloxy))-5-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide;
N-[3-((7 a S,2R)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizin-2-yloxy))-5-fluorophenyl]-N-hydroxy(3-pyridylamino)carboxamide; and
N-[3-((7 a S,2R)-6-methyl-5, 5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizin-2-yloxy))-5-fluorophenyl]-N-hydroxy[(6-methyl(3-pyridyl))amino]carboxamide.
6. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity of claim 1 .
7. The pharmaceutical composition of claim 6 wherein the composition is formulated in a form chosen from injectable fluids, aerosols, tablets, pills, capsules, syrups, creams, gels, and transdermal patches.