US2009176307A1PendingUtilityA1
Compounds, Compositions and Methods
Est. expiryJan 14, 2023(expired)· nominal 20-yr term from priority
Inventors:Bradley P. MorganKathleen Ann EliasErica Anne KraynackPu-Ping LuFady MalikAlex MuciXiangping QianWhitney W. SmithTodd TochimotoAdam Lewis TomasiDavid J. Morgans, Jr.
C07D 417/12C07C 275/40C07D 405/12A61P 41/00A61P 9/00A61P 43/00C07D 513/04C07D 213/65C07D 213/70C07D 213/75A61K 31/44C07D 217/04C07C 275/30C07C 275/36A61K 31/17C07D 207/12A61P 9/04C07D 498/04C07D 413/12C07D 211/42C07C 275/34C07D 401/12C07C 273/02
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 - 56 . (canceled)
56 . A method of potentiating the activity of cardiac myosin, comprising contacting said cardiac myosin with a compound of Formula I or a pharmaceutically acceptable salt thereof
wherein:
R 1 is represented by Formula II:
wherein:
R 1.1 is 1-acyl-pyrrolidin-3-yl, 1-alkoxycarbonyl-pyrrolidin-3-yl, 1-amidino-pyrrolidin-3-yl, 1-sulfonyl-pyrrolidin-3-yl, 3-oxo-tetrahydro-pyrrolo[1,2-c]oxazol-6-yl, 1-acyl-piperidin-3-yl, 1-alkoxycarbonyl-piperidin-3-yl, 1-amidino-piperidin-3-yl or 1-sulfonyl-piperidin-3-yl, each of which is optionally substituted with an additional lower alkoxy or lower alkoxyalkyl ring substituent; and
R 2 is pyridin-3-yl or pyridin-3-yl substituted with one or two substituents chosen from lower alkoxy and lower alkyl.
57 . The method of claim 56 where R 1.1 is 1-acetyl-piperidin-3-yl, 1-methoxyacetyl-piperidin-3-yl, 1-(azetidine-1-carbonyl)-piperidin-3-yl, 1-methoxycarbonyl-piperidin-3-yl, 1-ethoxycarbonyl-piperidin-3-yl, 1-dimethylaminocarbonyl-piperidin-3-yl, 1-methanesulfonyl-piperidin-3-yl, 1-(ethane-2-sulfonyl)-piperidin-3-yl, 1-(propane-2-sulfonyl)-piperidin-3-yl, 1-(azetidin-1-yl-sulfonyl)-piperidin-3-yl, 1-dimethylaminosulfonyl-piperidin-3-yl, 1-(N 1 -azetidin-1-yl-N 2 -cyano-amidino)-piperidin-3-yl, 1-(N 2 -cyano-N 1 ,N 1 -dimethyamidino)-piperidine-3-yl, 1-acetyl-pyrrolidin-3-yl, 1-acetyl-5-methoxymethyl-pyrrolidin-3-yl, 1-methoxyacetyl-pyrrolidin-3-yl, 1-(azetidine-1-carbonyl)-pyrrolidin-3-yl, 1-methoxycarbonyl-pyrrolidin-3-yl, 1-methoxycarbonyl-2-methoxymethyl-pyrrolidin-4-yl, 1-methanesulfonyl-pyrrolidin-3-yl, 1-(ethane-2-sulfonyl)-pyrrolidin-3-yl, 1-(ethane-2-sulfonyl)-4-methoxy-pyrrolidin-3-yl, 1-(ethane-2-sulfonyl)-5-methoxymethyl-pyrrolidin-3-yl, 1-(propane-2-sulfonyl)-pyrrolidin-3-yl, 1-(azetidin-1-yl-sulfonyl)-pyrrolidin-3-yl, 1-dimethylaminosulfonyl-pyrrolidin-3-yl, 1-dimethylaminosulfonyl-2-methoxymethyl-pyrrolidin-4-yl, 1-(N 1 -azetidin-1-yl-N 2 -cyano-amidino)-pyrrolidin-3-yl, 1-(N 2 -cyano-N 1 ,N 1 -dimethyamidino)-pyrrolidin-3-yl, or 3-oxo-tetrahydro-pyrrolo[1,2-c]oxazol-6-yl.
58 . The method of claim 56 where R 1.1 is 1-acyl-pyrrolidin-3-yl, 1-acetyl-5-methoxymethyl-pyrrolidin-3-yl, 1-sulfonyl-pyrrolidin-3-yl, 3-oxo-tetrahydro-pyrrolo[1,2-c]oxazol-6-yl, 1-alkoxycarbonyl-piperidin-3-yl or 1-sulfonyl-piperidin-3-yl.
59 . The method of claim 58 where R 1.1 is 1-methoxycarbonyl-2-methoxymethyl-pyrrolidin-4-yl, 1-(ethane-2-sulfonyl)-pyrrolidin-3-yl, 1-(ethane-2-sulfonyl)-5-methoxymethyl-pyrrolidin-3-yl, 1-dimethylaminosulfonyl-pyrrolidin-3-yl, 1-dimethylaminosulfonyl-2-methoxymethyl-pyrrolidin-4-yl, 3-oxo-tetrahydro-pyrrolo[1,2-c]oxazol-6-yl, 1-methoxycarbonyl-piperidin-3-yl, 1-methanesulfonyl-piperidin-3-yl, or 1-(ethane-2-sulfonyl)-piperidin-3-yl.
60 . The method of claim 56 where R 2 is pyridin-3-yl or 6-methyl-pyridin-3-yl.
61 . The method of claim 56 wherein the compound represented by Formula I is selected from:
1-[3-(1-Acetyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methoxy-pyridin-3-yl)-urea;
1-[3-(1-Acetyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-pyridin-3-yl-urea;
1-[3-Fluoro-5-(1-methanesulfonyl-piperidin-3-yloxy)-phenyl]-3-pyridin-3-yl-urea;
(R)-1-[3-(1-Acetyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methoxy-pyridin-3-yl)-urea;
(S)-1-[3-(1-Acetyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methoxy-pyridin-3-yl)-urea;
(R)-1-[3-(1-Acetyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-pyridin-3-yl-urea;
(S)-1-[3-(1-Acetyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-pyridin-3-yl-urea;
(R)-3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-piperidine-1-carboxylic acid methyl ester;
(S)-3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-piperidine-1-carboxylic acid methyl ester;
(R)-1-[3-Fluoro-5-(1-methanesulfonyl-piperidin-3-yloxy)-phenyl]-3-pyridin-3-yl-urea;
(S)-1-[3-Fluoro-5-(1-methanesulfonyl-piperidin-3-yloxy)-phenyl]-3-pyridin-3-yl-urea;
(R) —-[3-(1-Acetyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methyl-pyridin-3-yl)-urea;
(S)-1-[3-(1-Acetyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methyl-pyridin-3-yl)-urea;
(R)-1-[3-Fluoro-5-(1-methanesulfonyl-piperidin-3-yloxy)-phenyl]-3-(6-methyl-pyridin-3-yl)-urea;
(S)-1-[3-Fluoro-5-(1-methanesulfonyl-piperidin-3-yloxy)-phenyl]-3-(6-methyl-pyridin-3-yl)-urea;
(R)-1-{3-Fluoro-5-[1-(propane-2-sulfonyl)-piperidin-3-yloxy]-phenyl}-3-pyridin-3-yl-urea;
(S)-1-{3-Fluoro-5-[1-(propane-2-sulfonyl)-piperidin-3-yloxy]-phenyl}-3-pyridin-3-yl-urea;
(R)-1-{3-Fluoro-5-[1-(propane-2-sulfonyl)-piperidin-3-yloxy]-phenyl}-3-(6-methyl-pyridin-3-yl)-urea; ; :
(S)-1-{3-Fluoro-5-[1-(propane-2-sulfonyl)-piperidin-3-yloxy]-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(R)-1-[3-(1-ethanesulfonyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-pyridin-3-yl-urea;
(S)-1-[3-(1-ethanesulfonyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-pyridin-3-yl-urea;
(R)-1-[3-(1-Ethanesulfonyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methyl-pyridin-3-yl)-urea;
(S)-1-[3-(1-Ethanesulfonyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methyl-pyridin-3-yl)-urea;
(R)-3-[3-Fluoro-5-(pyridin-3-yl-ureido)-phenoxy]-piperidine-1-N,N-dimethyl-N-cyano-carboxamidine;
(S)-3-[3-Fluoro-5-(pyridin-3-yl-ureido)-phenoxy]-piperidine-1-N,N-dimethyl-N-cyano-carboxamidine;
(R)-3-[3-Fluoro-5-(2-methyl-pyridin-5-yl-ureido)-phenoxy]-piperidine-1-N ,N-dimethyl-N-cyano-carboxamidine;
(S)-3-[3-Fluoro-5-(2-methyl-pyridin-5-yl-ureido)-phenoxy]-piperidine-1-N,N-dimethyl-N-cyano-carboxamidine;
(R)-1-[3-(1-Ethanesulfonyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methyl-pydridin-3-yl)-urea;
(S)-1-[3-(1-Ethanesulfonyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methyl-pydridin-3-yl)-urea;
(R)-3-[3-Fluoro-5-(3-pyridin-3-yl-ureido)-phenoxy]-pyrrolidine-1-sulfonic acid dimethylamide;
(S)-3-[3-Fluoro-5-(3-pyridin-3-yl-ureido)-phenoxy]-pyrrolidine-1-sulfonic acid dimethylamide;
(R)-3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-pyrrolidine-1-sulfonic acid dimethylamide;
(S)-3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-y-)-ureido]-phenoxy}-pyrrolidine-1-sulfonic acid dimethylamide;
1-[(R)-3-(1-Acetyl-(R)-5-methoxymethyl-pyrrolidin-3-yloxy)-5-fluoro-phenyl]-3-pyridin-3-yl-urea;
1-[(S)-3-(1-Acetyl-(S)-5-methoxymethyl-pyrrolidin-3-yloxy)-5-fluoro-phenyl]-3-pyridin-3-yl-urea;
1-[(R)-3-(1-Acetyl-(S)-5-methoxymethyl-pyrrolidin-3-yloxy)-5-fluoro-phenyl]-3-pyridin-3-yl-urea;
1-[(S)-3-(1-Acetyl-(R)-5-methoxymethyl-pyrrolidin-3-yloxy)-5-fluoro-phenyl]-3-pyridin-3-yl-urea;
4-{3-fluoro-5-[(R)-3-(6-methyl-pyridin-3-yl)-ureido]phenoxy}-(R)-2-methoxymethyl-pyrrolidine-1-carboxylic acid methyl ester;
4-{3-fluoro-5-[(S)-3-(6-methyl-pyridin-3-yl)-ureido]phenoxy}-(S)-2-methoxymethyl-pyrrolidine-1-carboxylic acid methyl ester;
4-{3-fluoro-5-[(R)-3-(6-methyl-pyridin-3-yl)-ureido]phenoxy}-(S)-2-methoxymethyl-pyrrolidine-1-carboxylic acid methyl ester;
4-{3-fluoro-5-[(S)-3-(6-methyl-pyridin-3-yl)-ureido]phenoxy}-(R)-2-methoxymethyl-pyrrolidine-1-carboxylic acid methyl ester;
1-[(R)-3-(1-Acetyl-(R)-5-methoxymethyl-pyrrolidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methyl-pyridin-3-yl)-urea;
1-[(S)-3-(1-Acetyl-(S)-5-methoxymethyl-pyrrolidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methyl-pyridin-3-yl)-urea;
1-[(R)-3-(1-Acetyl-(S)-5-methoxymethyl-pyrrolidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methyl-pyridin-3-yl)-urea,
1-[(S)-3-(1-Acetyl-(R)-5-methoxymethyl-pyrrolidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methyl-pyridin-3-yl)-urea; and
3-[3-Fluoro-5-(3-pyridin-3-yl-ureido)-phenoxy]-piperidine-1-carboxylic acid methyl ester.
62 . The method of claim 56 wherein the compound represented by Formula I is selected from:
(S)-3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-pyrrolidine-1-sulfonic acid dimethylamide;
(R)-3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-pyrrolidine-1-sulfonic acid dimethylamide;
(S)-3-[3-Fluoro-5-(2-methyl-pyridin-5-yl-ureido)-phenoxy]-pyrrolidine-1-N,N-dimethyl-N-cyano-carboxamidine;
(R)-3-[3-Fluoro-5-(2-methyl-pyridin-5-yl-ureido)-phenoxy]-pyrrolidine-1-N,N-dimethyl-N-cyano-carboxamidine;
(S)-3-[3-Fluoro-5-(3-pyridin-3-yl-ureido)-phenoxy]-pyrrolidine-1-sulfonic acid dimethylamide;
(R)-3-[3-Fluoro-5-(3-pyridin-3-yl-ureido)-phenoxy]-pyrrolidine-1-sulfonic acid dimethylamide;
(S)-3-[3-Fluoro-5-(pyridin-2-yl-ureido)-phenoxy]-pyrrolidine-1-N,N-dimethyl-N-cyano-carboxamidine;
(R)-3-[3-Fluoro-5-(pyridin-2-yl-ureido)-phenoxy]-pyrrolidine-1-N,N-dimethyl-N-cyano-carboxamidine;
(S)-3-[3-Fluoro-5-(3-pyridin-3-yl-ureido)-phenoxy]-pyrrolidine-1-carboxylic acid methyl ester;
(R)-3-[3-Fluoro-5-(3-pyridin-3-yl-ureido)-phenoxy]-pyrrolidine-1-carboxylic acid methyl ester;
(S)-3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-pyrrolidine-1-carboxylic acid methyl ester;
(R)-3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-pyrrolidine-1-carboxylic acid methyl ester;
(S)-1-{3-Fluoro-5-[1-(propane-2-sulfonyl)-pyrrolidin-3-yloxy]-phenyl}-3-pyridin-3-yl-urea;
(R)-1-{3-Fluoro-5-[1-(propane-2-sulfonyl)-pyrrolidin-3-yloxy]-phenyl}-3-pyridin-3-yl-urea;
(S)-1-{3-Fluoro-5-[1-(propane-2-sulfonyl)-pyrrolidin-3-yloxy]-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(R)-1-{3-Fluoro-5-[1-(propane-2-sulfonyl)-pyrrolidin-3-yloxy]-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(S)-1-{3-Fluoro-5-[1-(ethane-2-sulfonyl)-pyrrolidin-3-yloxy]-phenyl}-3-pyridin-3-yl-urea;
(R)-1-{3-Fluoro-5-[1-(ethane-2-sulfonyl)-pyrrolidin-3-yloxy]-phenyl}-3-pyridin-3-yl-urea;
(S)-1-{3-Fluoro-5-[1-(ethane-2-sulfonyl)-pyrrolidin-3-yloxy]-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(R)-1-{3-Fluoro-5-[1-(ethane-2-sulfonyl)-pyrrolidin-3-yloxy]-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(S)-1-{3-Fluoro-5-[1-(methane-2-sulfonyl)-pyrrolidin-3-yloxy]-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(R)-1-{3-Fluoro-5-[1-(methane-2-sulfonyl)-pyrrolidin-3-yloxy]-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(S)-4-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-[(S)-2-methoxymethyl]-pyrrolidine-1-sulfonic acid dimethylamide;
(R)-4-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-[(R)-2-methoxymethyl]-pyrrolidine-1-sulfonic acid dimethylamide;
(S)-4-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-[(R)-2-methoxymethyl]-pyrrolidine-1-sulfonic acid dimethylamide;
(R)-4-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-[(S)-2-methoxymethyl]-pyrrolidine-1-sulfonic acid dimethylamide;
(S)-4-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-[(S)-2-methoxymethyl]-pyrrolidine-1-carboxylic acid methyl ester;
(R)-4-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-[(R)-2-methoxymethyl]-pyrrolidine-1-carboxylic acid methyl ester;
(S)-4-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-[(R)-2-methoxymethyl]-pyrrolidine-1-carboxylic acid methyl ester;
(R)-4-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-[(S)-2-methoxymethyl]-pyrrolidine-1-carboxylic acid methyl ester;
(S)-1-{3-(1-Ethanesulfonyl-[(S)-4-methoxy]-pyrrolidin-3-yloxy)-5-fluoro-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(R)-1-{3-(1-Ethanesulfonyl-[(R)-4-methoxy]-pyrrolidin-3-yloxy)-5-fluoro-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(S)-1-{3-(1-Ethanesulfonyl-[(R)-4-methoxy]-pyrrolidin-3-yloxy)-5-fluoro-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(R)-1-{3-(1-Ethanesulfonyl-[(S)-4-methoxy]-pyrrolidin-3-yloxy)-5-fluoro-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(S)-1-{3-(1-Ethanesulfonyl-[(S)-5-methoxymethyl]-pyrrolidin-3-yloxy)-5-fluoro-phenyl}-3-pyridin-3-yl-urea;
(R)-1-{3-(1-Ethanesulfonyl-[(R)-5-methoxymethyl]-pyrrolidin-3-yloxy)-5-fluoro-phenyl}-3-pyridin-3-yl-urea;
(S)-1-{3-(1-Ethanesulfonyl-[(R)-5-methoxymethyl]-pyrrolidin-3-yloxy)-5-fluoro-phenyl}-3-pyridin-3-yl-urea;
(R)-1-{3-(1-Ethanesulfonyl-[(S)-5-methoxymethyl]-pyrrolidin-3-yloxy)-5-fluoro-phenyl}-3-pyridin-3-yl-urea;
(S)-1-{3-(1-Ethanesulfonyl-[(S)-5-methoxymethyl]-pyrrolidin-3-yloxy)-5-fluoro-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(R)-1-{3-(1-Ethanesulfonyl-[(R)-5-methoxymethyl]-pyrrolidin-3-yloxy)-5-fluoro-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(S)-1-{3-(1-Ethanesulfonyl-[(R)-5-methoxymethyl]-pyrrolidin-3-yloxy)-5-fluoro-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(R)-1-{3-(1-Ethanesulfonyl-[(S)-5-methoxymethyl]-pyrrolidin-3-yloxy)-5-fluoro-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
1-[3-Fluoro-5-(S)-(3-oxo-(S)-tetrahydro-pyrrolo[1,2-c]oxazol-6-yloxy)-phenyl]-3-pyridin-3-yl-urea;
1-[3-Fluoro-5-(R)-(3-oxo-(R)-tetrahydro-pyrrolo[1,2-c]oxazol-6-yloxy)-phenyl]-3-pyridin-3-yl-urea;
1-[3-Fluoro-5-(S)-(3-oxo-(R)-tetrahydro-pyrrolo[1,2-c]oxazol-6-yloxy)-phenyl]-3-pyridin-3-yl-urea;
1-[3-Fluoro-5-(R)-(3-oxo-(S)-tetrahydro-pyrrolo[1,2-c]oxazol-6-yloxy)-phenyl]-3-pyridin-3-yl-urea;
1-[3-Fluoro-5-(S)-(3-oxo-(S)-tetrahydro-pyrrolo[1,2-c]oxazol-6-yloxy)-phenyl]-3-(6-methyl-pyridin-3-yl)-urea;
1-[3-Fluoro-5-(R)-(3-oxo-(R)-tetrahydro-pyrrolo[1,2-c]oxazol-6-yloxy)-phenyl]-3-(6-methyl-pyridin-3-yl)-urea;
1-[3-Fluoro-5-(S)-(3-oxo-(R)-tetrahydro-pyrrolo[1,2-c]oxazol-6-yloxy)-phenyl]-3-(6-methyl-pyridin-3-yl)-urea; and
1-[3-Fluoro-5-(R)-(3-oxo-(S)-tetrahydro-pyrrolo[1,2-c]oxazol-6-yloxy)-phenyl]-3-(6-methyl-pyridin-3-yl)-urea.
63 . The method of claim 56 wherein the compound represented by Formula I is selected from:
(R)-1-[3-(1-Acetyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-pyridin-3-yl-urea;
(R)-3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-piperidine-1-carboxylic acid methyl ester;
(S)-3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-piperidine-1-carboxylic acid methyl ester;
(S)-3-[3-Fluoro-5-(3-pyridin-3-yl-ureido)-phenoxy]-pyrrolidine-1-sulfonic acid dimethylamide;
1-[(R)-3-(1-Acetyl-(R)-5-methoxymethyl-pyrrolidin-3-yloxy)-5-fluoro-phenyl]-3-pyridin-3-yl-urea;
4-{3-fluoro-5-[(R)-3-(6-methyl-pyridin-3-yl)-ureido]phenoxy}-(R)-2-methoxymethyl-pyrrolidine-1-carboxylic acid methyl ester;
(S)-1-[3-(1-Ethanesulfonyl-piperidin-3-yloxy)-5-fluoro-phenyl]-3-(6-methyl-pydridin-3-yl)-urea;
(R)-1-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-piperidine-1-carboxylic acid methyl ester;
(S)-3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-piperidine-1-carboxylic acid methyl ester;
(S)-3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-pyrrolidine-1-carboxylic acid methyl ester;
(R)-3-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-pyrrolidine-1-carboxylic acid methyl ester;
(S)-1-[3-Fluoro-5-(1-methanesulfonyl-piperidin-3-yloxy)-phenyl]-3-pyridin-3-yl-urea;
(R)-3-[3-Fluoro-5-(3-pyridin-3-yl-ureido)-phenoxy]-pyrrolidine-1-sulfonic acid dimethylamide;
(R)-1-{3-Fluoro-5-[1-(ethane-2-sulfonyl)-pyrrolidin-3-yloxy]-phenyl}-3-(6-methyl-pyridin-3-yl)-urea;
(S)-4-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-[(S)-2-methoxymethyl]-pyrrolidine-1-sulfonic acid dimethylamide;
(S)-4-{3-Fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-[(S)-2-methoxymethyl]-pyrrolidine-1-carboxylic acid methyl ester;
(R)-1-{3-(1-Ethanesulfonyl-[(S)-5-methoxymethyl]-pyrrolidin-3-yloxy)-5-fluoro-phenyl}-3-pyridin-3-yl-urea;
1-[3-Fluoro-5-(R)-(3-oxo-(S)-tetrahydro-pyrrolo[1,2-c]oxazol-6-yloxy)-phenyl]-3-pyridin-3-yl-urea; and
1-[3-Fluoro-5-(R)-(3-oxo-(S)-tetrahydro-pyrrolo[1,2-c]oxazol-6-yloxy)-phenyl]-3-(6-methyl-pyridin-3-yl)-urea.
64 . A method of increasing the rate at which cardiac myosin hydrolyzes ATP, comprising contacting said cardiac myosin with a compound of Formula I or a pharmaceutically acceptable salt thereof
wherein:
R 1 is represented by Formula II:
wherein:
R 1.1 is 1-acyl-pyrrolidin-3-yl, 1-alkoxycarbonyl-pyrrolidin-3-yl, 1-amidino-pyrrolidin-3-yl, 1-sulfonyl-pyrrolidin-3-yl, 3-oxo-tetrahydro-pyrrolo[1,2-c]oxazol-6-yl, 1-acyl-piperidin-3-yl, 1-alkoxycarbonyl-piperidin-3-yl, 1-amidino-piperidin-3-yl or 1-sulfonyl-piperidin-3-yl, each of which is optionally substituted with an additional lower alkoxy or lower alkoxyalkyl ring substituent; and
R 2 is pyridin-3-yl or pyridin-3-yl substituted with one or two substituents chosen from lower alkoxy and lower alkyl.
65 . A method of increasing contractile force in cardiac muscle fiber, comprising contacting said cardiac muscle fiber with a compound of Formula I or a pharmaceutically acceptable salt thereof
wherein:
R 1 is represented by Formula II:
wherein:
R 1.1 is 1-acyl-pyrrolidin-3-yl, 1-alkoxycarbonyl-pyrrolidin-3-yl, 1-amidino-pyrrolidin-3-yl, 1-sulfonyl-pyrrolidin-3-yl, 3-oxo-tetrahydro-pyrrolo[1,2-c]oxazol-6-yl, 1-acyl-piperidin-3-yl, 1-alkoxycarbonyl-piperidin-3-yl, 1-amidino-piperidin-3-yl or 1-sulfonyl-piperidin-3-yl, each of which is optionally substituted with an additional lower alkoxy or lower alkoxyalkyl ring substituent; and
R 2 is pyridin-3-yl or pyridin-3-yl substituted with one or two substituents chosen from lower alkoxy and lower alkyl.Cited by (0)
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